US10988539B2 - Combination therapy with anti-HLA-DR antibodies and kinase inhibitors in hematopoietic cancers - Google Patents
Combination therapy with anti-HLA-DR antibodies and kinase inhibitors in hematopoietic cancers Download PDFInfo
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- US10988539B2 US10988539B2 US16/041,399 US201816041399A US10988539B2 US 10988539 B2 US10988539 B2 US 10988539B2 US 201816041399 A US201816041399 A US 201816041399A US 10988539 B2 US10988539 B2 US 10988539B2
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Definitions
- the present invention relates to therapeutic use in hematopoietic cancer of anti-HLA-DR antibodies or antibody-drug conjugates (ADCs), in combination with one or more kinase inhibitors, wherein the combination therapy is more effective than the antibody or ADC alone, kinase inhibitor alone, or the combined effects of kinase inhibitor and antibody or ADC alone.
- the combination exhibits synergistic effects.
- the kinase inhibitors of use are Bruton's kinase inhibitors or phosphoinositide 3-kinase (PI3K) inhibitors.
- the kinase inhibitors may be administered separately or together with the antibodies, or may be conjugated to the antibody prior to administration.
- the antibodies and kinase inhibitors may be linked via an intracellularly-cleavable linkage that increases therapeutic efficacy.
- the anti-HLA-DR antibody may be conjugated to a different drug (such as SN-38) to form an ADC, and the ADC may be administered in combination with a Bruton's kinase inhibitor or PI3K inhibitor.
- ADCs are administered at specific dosages and/or specific schedules of administration that optimize their therapeutic effect.
- an anti-HLA-DR antibody of use is IMMU-114 (hL243).
- Rituximab anti-CD20 IgG therapy is credited with revitalizing antibody therapies with its ability to effectively treat follicular lymphoma without the extensive side effects associated with more traditional chemotherapy regimens. Since rituximab's approval by the FDA in 1997, the mortality rate from NHL has declined by 2.8% per year (Molina, 2008, Ann Rev Med 59:237-50), and the use of this agent has been expanded to a variety of diseases.
- Rituximab was less effective in the more aggressive types of NHL, such as diffuse large B cell lymphoma (DLBCL), but when it was combined with combination chemotherapy, improved and durable objective responses compared to the separate therapies were found, making R-CHOP a standard protocol for the treatment of DLBCL (e.g., Leonard et al., 2008, Semin Hematol 45:S11-16; Friedberg et al., 2002, Br J Haematol 117:828-34).
- DLBCL diffuse large B cell lymphoma
- alemtuzumab anti-CD52 for chronic lymphocytic leukemia has been approved for use in hematologic malignancies (Robak, 2008, Curr Cancer Drug Targets 8:156-71).
- HLA-DR human leukocyte antigen-DR
- MHC major histocompatibilty complex
- HLA-DR is markedly more potent than other naked mAbs of current clinical interest in in vitro and in vivo experiments in lymphomas, leukemias, and multiple myeloma (Stein et al., unpublished results).
- HLA-DR is also expressed on a subset of normal immune cells, including B cells, monocytes/macrophages, Langerhans cells, dendritic cells, and activated T cells (Dechant et al., 2003, Semin Oncol 30:465-75).
- infusional toxicities likely related to complement activation, have been problematic clinically with the administration of anti-HLA-DR antibody (Shi et al., 2002, Leuk Lymphoma 43:1303-12.
- ALL acute lymphoblastic leukemia
- CLL chronic lymphocytic leukemia
- the invention involves combination therapy using an anti-HLA-DR antibody, or ADCs thereof, in combination with a kinase inhibitor selected from the group consisting of Bruton's kinase inhibitors and phosphoinositide 3-kinase (PI3K) inhibitors.
- a kinase inhibitor selected from the group consisting of Bruton's kinase inhibitors and phosphoinositide 3-kinase (PI3K) inhibitors.
- the combination therapy is more effective than antibody or ADC alone, kinase inhibitor alone, or the sum of the effects of antibody or ADC and kinase inhibitor.
- the combination exhibits synergistic effects for treatment of hematopoietic cancer in human subjects.
- the antibody is preferably conjugated to a CPT moiety, such as SN-38, or to an anthracycline, such as pro-2PDOX.
- CPT may refer to camptothecin or any of its derivatives, unless expressly stated otherwise.
- the camptothecin is SN-38.
- the anti-HLA-DR antibody can be of various isotypes, preferably human IgG1, IgG2, IgG3 or IgG4, more preferably comprising human IgG1 hinge and constant region sequences.
- the antibody or fragment thereof can be a chimeric human-mouse, a chimeric human-primate, a humanized (human framework and murine hypervariable (CDR) regions), or fully human antibody, as well as variations thereof, such as half-IgG4 antibodies (referred to as “unibodies”), as described by van der Neut Kolfschoten et al. ( Science 2007; 317:1554-1557).
- the antibody or fragment thereof may be designed or selected to comprise human constant region sequences that belong to specific allotypes, which may result in reduced immunogenicity when the antibody or ADC is administered to a human subject.
- Preferred allotypes for administration include a non-G1m1 allotype (nG1m1), such as G1m3, G1m3,1, G1m3,2 or G1m3,1,2. More preferably, the allotype is selected from the group consisting of the nG1m1, G1m3, nG1m1, 2 and Km3 allotypes.
- the antibody of use may bind to a tumor-associated antigen (TAA) other than HLA-DR.
- TAAs are known in the art, including but not limited to, carbonic anhydrase IX, alpha-fetoprotein (AFP), ⁇ -actinin-4, A3, antigen specific for A33 antibody, ART-4, B7, Ba 733, BAGE, BrE3-antigen, CA125, CAMEL, CAP-1, CASP-8/m, CCL19, CCL21, CD1, CD1a, CD2, CD3, CD4, CD S, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD44, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD66a-e, CD67, CD70, CD70L, CD74, CD79a,
- the antibody binds to CEACAM-5, CEACAM-6, EGP-1 (Trop-2), MUC-16, AFP, MUC5a,c, CD74, CD19, CD20, CD22 or HLA-DR.
- Exemplary antibodies that may be utilized in such alternative embodiments include, but are not limited to, hR1 (anti-IGF-1R, U.S. Pat. No. 9,441,043), hPAM4 (anti-mucin, U.S. Pat. No. 7,282,567), hA20 (anti-CD20, U.S. Pat. No. 7,151,164), hA19 (anti-CD19, U.S. Pat. No. 7,109,304), hIMMU31 (anti-AFP, U.S. Pat. No. 7,300,655), hLL1 (anti-CD74, U.S. Pat. No. 7,312,318), hLL2 (anti-CD22, U.S. Pat. No.
- hMu-9 anti-CSAp, U.S. Pat. No. 7,387,772
- hL243 anti-HLA-DR, U.S. Pat. No. 7,612,180
- hMN-14 anti-CEACAM-5, U.S. Pat. No. 6,676,924
- hMN-15 anti-CEACAM-6, U.S. Pat. No. 8,287,865
- hRS7 anti-EGP-1, U.S. Pat. No. 7,238,785
- hMN-3 anti-CEACAM-6, U.S. Pat. No. 7,541,440
- Ab124 and Ab125 anti-CXCR4, U.S. Pat. No.
- the antibody is IMMU-31 (anti-AFP), hRS7 (anti-Trop-2), hMN-14 (anti-CEACAM-5), hMN-3 (anti-CEACAM-6), hMN-15 (anti-CEACAM-6), hLL1 (anti-CD74), hLL2 (anti-CD22), hL243 or IMMU-114 (anti-HLA-DR), hA19 (anti-CD19) or hA20 (anti-CD20).
- the terms epratuzumab and hLL2 are interchangeable, as are the terms veltuzumab and hA20, hL243g4P, hL243gamma4P and IMMU-114.
- the antibody is an anti-Trop-2 antibody, such as hRS7, or an anti-HLA-DR antibody, such as hL243.
- Alternative antibodies of use include, but are not limited to, abciximab (anti-glycoprotein IIb/IIIa), alemtuzumab (anti-CD52), bevacizumab (anti-VEGF), cetuximab (anti-EGFR), gemtuzumab (anti-CD33), ibritumomab (anti-CD20), panitumumab (anti-EGFR), rituximab (anti-CD20), tositumomab (anti-CD20), trastuzumab (anti-ErbB2), lambrolizumab (anti-PD-1 receptor), atezolizumab (anti-PD-L1), MEDI4736 (anti-PD-L1), nivolumab (anti-PD-1 receptor), ipilimumab (anti-CTLA-4), abagovomab (anti-CA-125), adecatumumab (anti-EpCAM), atlizumab (anti-IL
- combination therapy with anti-HLA-DR antibody or ADC involves use of a kinase inhibitor, such as a Bruton's kinase inhibitor, e.g., ibrutinib (PCI-32765), PCI-45292, CC-292 (AVL-292), ONO-4059, GDC-0834, LFM-A13 or RN486, or a PI3K inhibitor, such as idelalisib, Wortmannin, demethoxyviridin, perifosine, PX-866, IPI-145 (duvelisib), BAY 80-6946, BEZ235, RP6530, TGR1202, SF1126, INK1117, GDC-0941, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115, CAL263, PI-103, GNE477,
- combination therapy may also involve administration of other drugs, either in unconjugated form or else conjugated to a subject antibody. It is contemplated within the scope of the invention that an anti-HLA-DR antibody or immunoconjugate, in combination with a kinase inhibitor, may be administered along with one or more additional therapeutic agents.
- the additional therapeutic agent is an anti-cancer drug
- it may be selected from the group consisting of 5-fluorouracil, afatinib, aplidin, azaribine, anastrozole, anthracyclines, axitinib, AVL-101, AVL-291, bendamustine, bleomycin, bortezomib, bosutinib, bryostatin-1, busulfan, calicheamycin, camptothecin, carboplatin, 10-hydroxycamptothecin, carmustine, celebrex, chlorambucil, cisplatin (CDDP), Cox-2 inhibitors, irinotecan (CPT-11), SN-38, carboplatin, cladribine, camptothecans, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dasatinib, dinaciclib, docetaxel, dactinomycin,
- anti-HLA-DR may be administered in combination with a PI3K inhibitor, such as idelalisib, Wortmannin, demethoxyviridin, perifosine, PX-866, IPI-145 (duvelisib), BAY 80-6946, BEZ235, RP6530, TGR1202, SF1126, INK1117, GDC-0941, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115, CAL263, PI-103, GNE477, CUDC-907, AEZS-136 or LY294002.
- a PI3K inhibitor such as idelalisib, Wortmannin, demethoxyviridin, perifosine, PX-866, IPI-145 (duvelisib), BAY 80-6946, BEZ235, RP6530, TGR1202,
- the combination therapy may include use of a microtubule inhibitor, such as vinca alkaloids (e.g., vincristine, vinblastine), taxanes (e.g., paclitaxel), maytansinoids (e.g., mertansine) and auristatins.
- a microtubule inhibitor such as vinca alkaloids (e.g., vincristine, vinblastine), taxanes (e.g., paclitaxel), maytansinoids (e.g., mertansine) and auristatins.
- microtubule inhibitors include demecolcine, nocodazole, epothilone, docetaxel, discodermolide, colchicine, combrestatin, podophyllotoxin, CI-980, phenylahistins, steganacins, curacins, 2-methoxy estradiol, E7010, methoxy benzenesuflonamides, vinorelbine, vinflunine, vindesine, dolastatins, spongistatin, rhizoxin, tasidotin, halichondrins, hemiasterlins, cryptophycin 52, MMAE and eribulin mesylate (see, e.g., Dumontet & Jordan, 2010, Nat Rev Drug Discov 9:790-803).
- such conjugated drugs may be selected from camptothecin (CPT) and its analogs and derivatives and is more preferably SN-38.
- CPT camptothecin
- other drug moieties include taxanes (e.g., baccatin III, taxol), auristatins (e.g., MMAE), calicheamicins, epothilones, anthracyclines (e.g., doxorubicin (DOX), epirubicin, morpholinodoxorubicin (morpholino-DOX), cyanomorpholino-doxorubicin (cyanomorpholino-DOX), 2-pyrrolinodoxorubicin (2-PDOX), a prodrug form of 2-PDOX (pro-2-PDOX), topotecan, etoposide, cisplatinum, oxaliplatin or carboplatin; see, e.g., Prie
- the antibody or fragment thereof links to at least one chemotherapeutic moiety; preferably 1 to about 5 drug moieties; more preferably 6 to about 12 drug moieties, most preferably about 6 to 8 drug moieties.
- a chemotherapeutic moiety preferably 1 to about 5 drug moieties; more preferably 6 to about 12 drug moieties, most preferably about 6 to 8 drug moieties.
- an anti-HLA-DR (hL243) antibody is conjugated to an SN-38 moiety
- the conjugate may be referred to as IMMU-140.
- CPT-11 water soluble CPT derivative
- Extensive clinical data are available concerning CPT-11's pharmacology and its in vivo conversion to the active SN-38 (Iyer and Ratain, Cancer Chemother Pharmacol. 42:S31-43 (1998); Mathijssen et al., Clin Cancer Res. 7:2182-2194 (2002); Rivory, Ann NY Acad Sci. 922:205-215, 2000)).
- the active form SN-38 is about 2 to 3 orders of magnitude more potent than CPT-11.
- the ADC may be an hMN-14-SN-38 (IMMU-130), hMN-3-SN-38, hMN-15-SN-38, IMMU-31-SN-38, hRS7-SN-38 (IMMU-132), hA20-SN-38, IMMU-140 (IMMU-140), hLL1-SN-38 or hLL2-SN-38 conjugate.
- IMMU-130 hMN-14-SN-38
- hMN-3-SN-38 hMN-15-SN-38
- IMMU-31-SN-38 hRS7-SN-38
- IMMU-132 hA20-SN-38
- IMMU-140 IMMU-140
- hLL1-SN-38 or hLL2-SN-38 conjugate.
- Various embodiments may concern use of the subject methods and compositions to treat a cancer, including but not limited to non-Hodgkin's lymphomas, B-cell acute and chronic lymphoid leukemias, Burkitt lymphoma, Hodgkin's lymphoma, acute large B-cell lymphoma, hairy cell leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, T-cell lymphomas and leukemias, multiple myeloma, cancers of the skin, esophagus, stomach, colon, rectum, pancreas, lung, breast, ovary, bladder, endometrium, cervix, testes, kidney, liver, melanoma or other HLA-DR-producing tumors.
- non-Hodgkin's lymphomas B-cell acute and chronic lymphoid leukemias, Burkitt lymphoma
- the antibodies or ADCs and kinase inhibitors may be used in combination with a standard anti-cancer therapy, such as surgery, radiation therapy, chemotherapy, immunotherapy with naked antibodies, including checkpoint-inhibiting antibodies, radioimmunotherapy, immunomodulators, vaccines, and the like.
- the claimed methods provide for shrinkage of solid tumors, in individuals with previously resistant cancers, of 15% or more, preferably 20% or more, preferably 30% or more, more preferably 40% or more in size (as measured by summing the longest diameter of target lesions, as per RECIST or RECIST 1.1).
- tumor size may be measured by a variety of different techniques, such as total tumor volume, maximal tumor size in any dimension or a combination of size measurements in several dimensions. This may be with standard radiological procedures, such as computed tomography, magnet resonance imaging, ultrasonography, and/or positron-emission tomography.
- the means of measuring size is less important than observing a trend of decreasing tumor size with combination therapy, preferably resulting in elimination of the tumor.
- CT or MRI is preferred on a serial basis, and should be repeated to confirm measurements.
- FIG. 1 Comparative efficacies of anti-HLA-DR (IMMU-114) and anti-CD20 (rituximab) unconjugated antibodies for treatment of CLL xenografts. Experiment was performed as disclosed in Example 1.
- FIG. 2 Survival curves for CLL xenografted nude mice treated with unconjugated antibodies. Mice bearing JVM-3 xenografts were treated with unconjugated rituximab or IMMU-114, as disclosed in Example 1.
- FIG. 3 Dose-response curves for IMMU-114 at constant ibrutinib.
- FIG. 4 Dose-response curves for ibrutinib at constant IMMU-114.
- FIG. 5 Isobologram showing synergistic effect of IMMU-114 in combination with a Bruton's tyrosine kinase inhibitor.
- FIG. 6 Dose-response curves for idelalisib at constant IMMU-114.
- FIG. 7 Isobologram for the PI3K inhibitor idelalisib in combination with IMMU-114.
- FIG. 8 Survival curves comparing the efficacy of IMMU-114 vs. doxorubicin in nude mice with ALL xenografts.
- FIG. 9 Survival curves for mice bearing disseminated acute myeloid leukemia xenografts, treated with IMMU-114 (hL243) vs. IMMU-140 (hL243-SN-38).
- FIG. 10 Survival curves for mice bearing disseminated acute lymphocytic leukemia xenografts, treated with IMMU-114 (hL243) vs. IMMU-140 (hL243-SN-38).
- FIG. 11 Survival curves for mice bearing disseminated multiple myeloma xenografts, treated with IMMU-114 (hL243) vs. IMMU-140 (hL243-SN-38).
- a or an means “one or more.”
- an antibody refers to a full-length (i.e., naturally occurring or formed by normal immunoglobulin gene fragment recombinatorial processes) immunoglobulin molecule (e.g., an IgG antibody) or an antigen-binding portion of an immunoglobulin molecule, such as an antibody fragment.
- An antibody or antibody fragment may be conjugated or otherwise derivatized within the scope of the claimed subject matter.
- Such antibodies include but are not limited to IgG1, IgG2, IgG3, IgG4 (and IgG4 subforms), as well as IgA isotypes.
- the abbreviation “MAb” may be used interchangeably to refer to an antibody, antibody fragment, monoclonal antibody or multispecific antibody.
- An antibody fragment is a portion of an antibody such as F(ab′) 2 , F(ab) 2 , Fab′, Fab, Fv, scFv (single chain Fv), single domain antibodies (DABs or VHHs) and the like, including the half-molecules of IgG4 cited above (van der Neut Kolfschoten et al. (Science 2007; 317(14 September):1554-1557). Regardless of structure, an antibody fragment of use binds with the same antigen that is recognized by the intact antibody.
- the term “antibody fragment” also includes synthetic or genetically engineered proteins that act like an antibody by binding to a specific antigen to form a complex.
- antibody fragments include isolated fragments consisting of the variable regions, such as the “Fv” fragments consisting of the variable regions of the heavy and light chains and recombinant single chain polypeptide molecules in which light and heavy variable regions are connected by a peptide linker (“scFv proteins”).
- the fragments may be constructed in different ways to yield multivalent and/or multispecific binding forms.
- a naked antibody is generally an entire antibody that is not conjugated to a therapeutic agent.
- a naked antibody may exhibit therapeutic and/or cytotoxic effects, for example by Fc-dependent functions, such as complement fixation (CDC) and ADCC (antibody-dependent cell cytotoxicity).
- Fc-dependent functions such as complement fixation (CDC) and ADCC (antibody-dependent cell cytotoxicity).
- other mechanisms such as apoptosis, anti-angiogenesis, anti-metastatic activity, anti-adhesion activity, inhibition of heterotypic or homotypic adhesion, and interference in signaling pathways, may also provide a therapeutic effect.
- Naked antibodies include polyclonal and monoclonal antibodies, naturally occurring or recombinant antibodies, such as chimeric, humanized or human antibodies and fragments thereof. In some cases a “naked antibody” may also refer to a “naked” antibody fragment. As defined herein, “naked” is synonymous with “unconjugated,” and means not linked or conjugated to a therapeutic agent.
- a chimeric antibody is a recombinant protein that contains the variable domains of both the heavy and light antibody chains, including the complementarity determining regions (CDRs) of an antibody derived from one species, preferably a rodent antibody, more preferably a murine antibody, while the constant domains of the antibody molecule are derived from those of a human antibody.
- CDRs complementarity determining regions
- the constant domains of the chimeric antibody may be derived from that of other species, such as a primate, cat or dog.
- a humanized antibody is a recombinant protein in which the CDRs from an antibody from one species; e.g., a murine antibody, are transferred from the heavy and light variable chains of the murine antibody into human heavy and light variable domains (framework regions).
- the constant domains of the antibody molecule are derived from those of a human antibody.
- specific residues of the framework region of the humanized antibody particularly those that are touching or close to the CDR sequences, may be modified, for example replaced with the corresponding residues from the original murine, rodent, subhuman primate, or other antibody.
- a human antibody is an antibody obtained, for example, from transgenic mice that have been “engineered” to produce human antibodies in response to antigenic challenge.
- elements of the human heavy and light chain loci are introduced into strains of mice derived from embryonic stem cell lines that contain targeted disruptions of the endogenous heavy chain and light chain loci.
- the transgenic mice can synthesize human antibodies specific for various antigens, and the mice can be used to produce human antibody-secreting hybridomas.
- Methods for obtaining human antibodies from transgenic mice are described by Green et al., Nature Genet. 7:13 (1994), Lonberg et al., Nature 368:856 (1994), and Taylor et al., Int. Immun. 6:579 (1994).
- a fully human antibody also can be constructed by genetic or chromosomal transfection methods, as well as phage display technology, all of which are known in the art. See for example, McCafferty et al., Nature 348:552-553 (1990) for the production of human antibodies and fragments thereof in vitro, from immunoglobulin variable domain gene repertoires from unimmunized donors.
- human antibody variable domain genes are cloned in-frame into either a major or minor coat protein gene of a filamentous bacteriophage, and displayed as functional antibody fragments on the surface of the phage particle.
- the filamentous particle contains a single-stranded DNA copy of the phage genome, selections based on the functional properties of the antibody also result in selection of the gene encoding the antibody exhibiting those properties. In this way, the phage mimics some of the properties of the B cell.
- Phage display can be performed in a variety of formats, for their review, see e.g. Johnson and Chiswell, Current Opinion in Structural Biology 3:5564-571 (1993).
- Human antibodies may also be generated by in vitro activated B cells. See U.S. Pat. Nos. 5,567,610 and 5,229,275, the Examples section of each of which is incorporated herein by reference.
- a therapeutic agent is an atom, molecule, or compound that is useful in the treatment of a disease.
- therapeutic agents include, but are not limited to, antibodies, antibody fragments, ADCs, drugs, cytotoxic agents, pro-apopoptotic agents, toxins, nucleases (including DNAses and RNAses), hormones, immunomodulators, chelators, boron compounds, photoactive agents or dyes, radionuclides, oligonucleotides, interference RNA, siRNA, RNAi, anti-angiogenic agents, chemotherapeutic agents, cyokines, chemokines, prodrugs, enzymes, binding proteins or peptides or combinations thereof.
- An ADC is an antibody, antigen-binding antibody fragment, antibody complex or antibody fusion protein that is conjugated to at least one therapeutic agent. Conjugation may be covalent or non-covalent. Preferably, conjugation is covalent.
- the term antibody fusion protein is a recombinantly-produced antigen-binding molecule in which one or more natural antibodies, single-chain antibodies or antibody fragments are linked to another moiety, such as a protein or peptide, a toxin, a cytokine, a hormone, etc.
- the fusion protein may comprise two or more of the same or different antibodies, antibody fragments or single-chain antibodies fused together, which may bind to the same epitope, different epitopes on the same antigen, or different antigens.
- An immunomodulator is a therapeutic agent that when present, alters, suppresses or stimulates the body's immune system.
- an immunomodulator of use stimulates immune cells to proliferate or become activated in an immune response cascade, such as macrophages, dendritic cells, B-cells, and/or T-cells.
- an immunomodulator may suppress proliferation or activation of immune cells.
- An example of an immunomodulator as described herein is a cytokine, which is a soluble small protein of approximately 5-20 kDa that is released by one cell population (e.g., primed T-lymphocytes) on contact with specific antigens, and which acts as an intercellular mediator between cells.
- cytokines include lymphokines, monokines, interleukins, and several related signaling molecules, such as tumor necrosis factor (TNF) and interferons.
- TNF tumor necrosis factor
- cytokines are a subset of cytokines.
- Certain interleukins and interferons are examples of cytokines that stimulate T cell or other immune cell proliferation.
- Exemplary interferons include interferon- ⁇ , interferon- ⁇ , interferon- ⁇ and interferon- ⁇ .
- monoclonal antibodies can be obtained by injecting mice with a composition comprising an antigen, removing the spleen to obtain B-lymphocytes, fusing the B-lymphocytes with myeloma cells to produce hybridomas, cloning the hybridomas, selecting positive clones which produce antibodies to the antigen, culturing the clones that produce antibodies to the antigen, and isolating the antibodies from the hybridoma cultures.
- MAbs can be isolated and purified from hybridoma cultures by a variety of well-established techniques. Such isolation techniques include affinity chromatography with Protein-A or Protein-G Sepharose, size-exclusion chromatography, and ion-exchange chromatography. See, for example, Coligan at pages 2.7.1-2.7.12 and pages 2.9.1-2.9.3. Also, see Baines et al., “Purification of Immunoglobulin G (IgG),” in METHODS IN MOLECULAR BIOLOGY, VOL. 10, pages 79-104 (The Humana Press, Inc. 1992).
- the antibodies can be sequenced and subsequently prepared by recombinant techniques. Humanization and chimerization of murine antibodies and antibody fragments are well known to those skilled in the art, as discussed below.
- Antibodies of use may be commercially obtained from a wide variety of known sources.
- a variety of antibody secreting hybridoma lines are available from the American Type Culture Collection (ATCC, Manassas, Va.).
- a large number of antibodies against various disease targets, including but not limited to tumor-associated antigens, have been deposited at the ATCC and/or have published variable region sequences and are available for use in the claimed methods and compositions. See, e.g., U.S. Pat. Nos.
- antibody sequences or antibody-secreting hybridomas against almost any disease-associated antigen may be obtained by a simple search of the ATCC, NCBI and/or USPTO databases for antibodies against a selected disease-associated target of interest.
- the antigen binding domains of the cloned antibodies may be amplified, excised, ligated into an expression vector, transfected into an adapted host cell and used for protein production, using standard techniques well known in the art.
- Isolated antibodies may be conjugated to therapeutic agents that induce DNA strand breaks, such as camptothecins or anthracyclines, using the techniques disclosed herein.
- a chimeric antibody is a recombinant protein in which the variable regions of a human antibody have been replaced by the variable regions of, for example, a mouse antibody, including the complementarity-determining regions (CDRs) of the mouse antibody.
- Chimeric antibodies exhibit decreased immunogenicity and increased stability when administered to a subject.
- Methods for constructing chimeric antibodies are well known in the art (e.g., Leung et al., 1994, Hybridoma 13:469).
- a chimeric monoclonal antibody may be humanized by transferring the mouse CDRs from the heavy and light variable chains of the mouse immunoglobulin into the corresponding variable domains of a human antibody.
- the mouse framework regions (FR) in the chimeric monoclonal antibody are also replaced with human FR sequences.
- one or more human FR residues may be replaced by the mouse counterpart residues.
- Humanized monoclonal antibodies may be used for therapeutic treatment of subjects. Techniques for production of humanized monoclonal antibodies are well known in the art.
- an antibody may be a human monoclonal antibody. Such antibodies may be obtained from transgenic mice that have been engineered to produce specific human antibodies in response to antigenic challenge, as discussed below.
- the phage display technique may be used to generate human antibodies (e.g., Dantas-Barbosa et al., 2005, Genet. Mol. Res. 4:126-40, incorporated herein by reference).
- Human antibodies may be generated from normal humans or from humans that exhibit a particular disease state, such as cancer (Dantas-Barbosa et al., 2005).
- the advantage to constructing human antibodies from a diseased individual is that the circulating antibody repertoire may be biased towards antibodies against disease-associated antigens.
- RNAs were converted to cDNAs and used to make Fab cDNA libraries using specific primers against the heavy and light chain immunoglobulin sequences (Marks et al., 1991, J. Mol. Biol. 222:581-97, incorporated herein by reference).
- transgenic animals that have been genetically engineered to produce human antibodies may be used to generate antibodies against essentially any immunogenic target, using standard immunization protocols as discussed above.
- Methods for obtaining human antibodies from transgenic mice are described by Green et al., Nature Genet. 7:13 (1994), Lonberg et al., Nature 368:856 (1994), and Taylor et al., Int. Immun. 6:579 (1994).
- a non-limiting example of such a system is the XENOMOUSE® (e.g., Green et al., 1999, J. Immunol. Methods 231:11-23, incorporated herein by reference) from Abgenix (Fremont, Calif.).
- the mouse antibody genes have been inactivated and replaced by functional human antibody genes, while the remainder of the mouse immune system remains intact.
- the XENOMOUSE® was transformed with germline-configured YACs (yeast artificial chromosomes) that contained portions of the human IgH and Ig kappa loci, including the majority of the variable region sequences, along accessory genes and regulatory sequences.
- the human variable region repertoire may be used to generate antibody producing B cells, which may be processed into hybridomas by known techniques.
- a XENOMOUSE® immunized with a target antigen will produce human antibodies by the normal immune response, which may be harvested and/or produced by standard techniques discussed above.
- a variety of strains of XENOMOUSE® are available, each of which is capable of producing a different class of antibody.
- Transgenically produced human antibodies have been shown to have therapeutic potential, while retaining the pharmacokinetic properties of normal human antibodies (Green et al., 1999).
- the skilled artisan will realize that the claimed compositions and methods are not limited to use of the XENOMOUSE® system but may utilize any transgenic animal that has been genetically engineered to produce human antibodies.
- Some embodiments of the claimed methods and/or compositions may concern antibody fragments.
- Such antibody fragments may be obtained, for example, by pepsin or papain digestion of whole antibodies by conventional methods.
- antibody fragments may be produced by enzymatic cleavage of antibodies with pepsin to provide a 5S fragment denoted F(ab′) 2 .
- This fragment may be further cleaved using a thiol reducing agent and, optionally, a blocking group for the sulfhydryl groups resulting from cleavage of disulfide linkages, to produce 3.5S Fab′ monovalent fragments.
- an enzymatic cleavage using pepsin produces two monovalent Fab fragments and an Fc fragment.
- Fv fragments comprise an association of V H and V L chains. This association can be noncovalent, as described in Inbar et al., 1972, Proc. Nat'l. Acad. Sci. USA, 69:2659.
- the variable chains may be linked by an intermolecular disulfide bond or cross-linked by chemicals such as glutaraldehyde. See Sandhu, 1992, Crit. Rev. Biotech., 12:437.
- the Fv fragments comprise V H and V L chains connected by a peptide linker.
- These single-chain antigen binding proteins are prepared by constructing a structural gene comprising DNA sequences encoding the V H and V L domains, connected by an oligonucleotides linker sequence. The structural gene is inserted into an expression vector that is subsequently introduced into a host cell, such as E. coli . The recombinant host cells synthesize a single polypeptide chain with a linker peptide bridging the two V domains. Methods for producing scFvs are well-known in the art.
- an antibody fragment is a single-domain antibody (dAb), sometimes referred to as a single chain antibody.
- Techniques for producing single-domain antibodies are well known in the art (see, e.g., Cossins et al., Protein Expression and Purification, 2007, 51:253-59; Shuntao et al., Molec Immunol 2006, 43:1912-19; Tanha et al., J. Biol. Chem. 2001, 276:24774-780).
- Other types of antibody fragments may comprise one or more complementarity-determining regions (CDRs).
- CDR peptides (“minimal recognition units”) can be obtained by constructing genes encoding the CDR of an antibody of interest.
- Such genes are prepared, for example, by using the polymerase chain reaction to synthesize the variable region from RNA of antibody-producing cells. See Larrick et al., 1991, Methods: A Companion to Methods in Enzymology 2:106; Ritter et al. (eds.), 1995, MONOCLONAL ANTIBODIES: PRODUCTION, ENGINEERING AND CLINICAL APPLICATION, pages 166-179 (Cambridge University Press); Birch et al., (eds.), 1995, MONOCLONAL ANTIBODIES: PRINCIPLES AND APPLICATIONS, pages 137-185 (Wiley-Liss, Inc.)
- the sequences of antibodies may be varied to optimize the physiological characteristics of the conjugates, such as the half-life in serum.
- Methods of substituting amino acid sequences in proteins are widely known in the art, such as by site-directed mutagenesis (e.g. Sambrook et al., Molecular Cloning, A laboratory manual, 2 nd Ed, 1989).
- the variation may involve the addition or removal of one or more glycosylation sites in the Fc sequence (e.g., U.S. Pat. No. 6,254,868, the Examples section of which is incorporated herein by reference).
- specific amino acid substitutions in the Fc sequence may be made (e.g., Hornick et al., 2000, J Nucl Med 41:355-62; Hinton et al., 2006, J Immunol 176:346-56; Petkova et al. 2006, Int Immunol 18:1759-69; U.S. Pat. No. 7,217,797; each incorporated herein by reference).
- the antibody of use is targeted to the human HLA-DR antigen.
- antibodies may be used that recognize and/or bind to human antigens that are expressed at high levels on target cells and that are expressed predominantly or exclusively on diseased cells versus normal tissues. More preferably, the antibodies internalize rapidly following binding.
- An exemplary rapidly internalizing antibody is the LL1 (anti-CD74) antibody, with a rate of internalization of approximately 8 ⁇ 10 6 antibody molecules per cell per day (e.g., Hansen et al., 1996 , Biochem J. 320:293-300).
- a “rapidly internalizing” antibody may be one with an internalization rate of about 1 ⁇ 10 6 to about 1 ⁇ 10 7 antibody molecules per cell per day.
- Antibodies of use in the claimed compositions and methods may include MAbs with properties as recited above.
- Exemplary antibodies of use for therapy of, for example, cancer include but are not limited to LL1 (anti-CD74), LL2 or RFB4 (anti-CD22), veltuzumab (hA20, anti-CD20), rituxumab (anti-CD20), obinutuzumab (GA101, anti-CD20), lambrolizumab (anti-PD-1 receptor), nivolumab (anti-PD-1 receptor), ipilimumab (anti-CTLA-4), RS7 (anti-Trop-2), PAM4 (aka clivatuzumab, anti-MUC-5ac), MN-14 (anti-CEACAM-5), MN-15 or MN-3 (anti-CEACAM-6), Mu-9 (anti-colon-specific antigen-p), Immu 31 (an anti-alpha-fetoprotein), R1 (anti-IGF-1R),
- hPAM4 U.S. Pat. No. 7,282,567
- hA20 U.S. Pat. No. 7,151,164
- hA19 U.S. Pat. No. 7,109,304
- hIMMU-31 U.S. Pat. No. 7,300,655
- hLL1 U.S. Pat. No. 7,312,318,
- hLL2 U.S. Pat. No. 5,789,554
- hMu-9 U.S. Pat. No. 7,387,772
- hL243 U.S. Pat. No.
- antigens that may be targeted include carbonic anhydrase IX, B7, CCL19, CCL21, CSAp, HER-2/neu, BrE3, CD1, CD1a, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20 (e.g., C2B8, hA20, 1F5 MAbs), CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD44, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD67, CD70, CD74, CD79a, CD80, CD83, CD95, CD126, CD133, CD138, CD147, CD154, CEACAM-5, CEACAM-6, CTLA-4, alpha-fetoprotein (AFP), VEGF (e.g., AVASTIN®, fibronectin splice variant), ED-B
- CD Cluster Designation
- the CD66 antigens consist of five different glycoproteins with similar structures, CD66a-e, encoded by the carcinoembryonic antigen (CEA) gene family members, BCG, CGM6, NCA, CGMI and CEA, respectively. These CD66 antigens (e.g., CEACAM-6) are expressed mainly in granulocytes, normal epithelial cells of the digestive tract and tumor cells of various tissues. Also included as suitable targets for cancers are cancer testis antigens, such as NY-ESO-1 (Theurillat et al., Int. J. Cancer 2007; 120(11):2411-7), as well as CD79a in myeloid leukemia (Kozlov et al., Cancer Genet. Cytogenet.
- suitable targeting antibodies have been described against, for example, CD38 and CD138 (Stevenson, Mol Med 2006; 12(11-12):345-346; Tassone et al., Blood 2004; 104(12):3688-96), CD74 (Stein et al., ibid.), CS1 (Tai et al., Blood 2008; 112(4):1329-37, and CD40 (Tai et al., 2005; Cancer Res. 65(13):5898-5906).
- Macrophage migration inhibitory factor is an important regulator of innate and adaptive immunity and apoptosis. It has been reported that CD74 is the endogenous receptor for MIF (Leng et al., 2003, J Exp Med 197:1467-76).
- the therapeutic effect of antagonistic anti-CD74 antibodies on MIF-mediated intracellular pathways may be of use for treatment of a broad range of disease states, such as cancers of the bladder, prostate, breast, lung, colon and chronic lymphocytic leukemia (e.g., Meyer-Siegler et al., 2004, BMC Cancer 12:34; Shachar & Haran, 2011, Leuk Lymphoma 52:1446-54); autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus (Morand & Leech, 2005, Front Biosci 10:12-22; Shachar & Haran, 2011, Leuk Lymphoma 52:1446-54); kidney diseases such as renal allograft rejection (Lan, 2008, Nephron Exp Nephrol.
- a broad range of disease states such as cancers of the bladder, prostate, breast, lung, colon and chronic lymphocytic leukemia (e.g., Meyer-Siegler et al., 2004, BMC Cancer 12
- Anti-TNF- ⁇ antibodies are known in the art and may be of use to treat immune diseases, such as autoimmune disease, immune dysfunction (e.g., graft-versus-host disease, organ transplant rejection) or diabetes.
- Known antibodies against TNF- ⁇ include the human antibody CDP571 (Ofei et al., 2011, Diabetes 45:881-85); murine antibodies MTNFAI, M2TNFAI, M3TNFAI, M3TNFABI, M302B and M303 (Thermo Scientific, Rockford, Ill.); infliximab (Centocor, Malvern, Pa.); certolizumab pegol (UCB, Brussels, Belgium); and adalimumab (Abbott, Abbott Park, Ill.).
- anti-B-cell antibodies such as veltuzumab, epratuzumab, milatuzumab or hL243; tocilizumab (anti-IL-6 receptor); basiliximab (anti-CD25); daclizumab (anti-CD25); efalizumab (anti-CD11a); muromonab-CD3 (anti-CD3 receptor); anti-CD40L (UCB, Brussels, Belgium); natalizumab (anti- ⁇ 4 integrin) and omalizumab (anti-IgE).
- anti-B-cell antibodies such as veltuzumab, epratuzumab, milatuzumab or hL243; tocilizumab (anti-IL-6 receptor); basiliximab (anti-CD25); daclizumab (anti-CD25); efalizumab (anti-CD11a); muromonab-CD3 (anti-CD3 receptor); anti-CD40L (UCB,
- antibodies are used that internalize rapidly and are then re-expressed, processed and presented on cell surfaces, enabling continual uptake and accretion of circulating conjugate by the cell.
- An example of a most-preferred antibody/antigen pair is LL1, an anti-CD74 MAb (invariant chain, class II-specific chaperone, Ii) (see, e.g., U.S. Pat. Nos. 6,653,104; 7,312,318; the Examples section of each incorporated herein by reference).
- the CD74 antigen is highly expressed on B-cell lymphomas (including multiple myeloma) and leukemias, certain T-cell lymphomas, melanomas, colonic, lung, and renal cancers, glioblastomas, and certain other cancers (Ong et al., Immunology 98:296-302 (1999)).
- B-cell lymphomas including multiple myeloma
- leukemias certain T-cell lymphomas
- melanomas melanomas
- colonic, lung, and renal cancers glioblastomas
- glioblastomas and certain other cancers
- the diseases that are preferably treated with anti-CD74 antibodies include, but are not limited to, non-Hodgkin's lymphoma, Hodgkin's disease, melanoma, lung, renal, colonic cancers, glioblastome multiforme, histiocytomas, myeloid leukemias, and multiple myeloma.
- Continual expression of the CD74 antigen for short periods of time on the surface of target cells, followed by internalization of the antigen, and re-expression of the antigen enables the targeting LL1 antibody to be internalized along with any drug moiety it carries. This allows a high, and therapeutic, concentration of LL1-drug conjugate to be accumulated inside such cells. Internalized LL1-drug conjugates are cycled through lysosomes and endosomes, and the drug moiety is released in an active form within the target cells.
- Antibodies of use to treat autoimmune disease or immune system dysfunctions are known in the art and may be conjugated to SN-38 using the disclosed methods and compositions.
- Antibodies of use to treat autoimmune/immune dysfunction disease may bind to exemplary antigens including, but not limited to, BCL-1, BCL-2, BCL-6, CD1a, CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD11b, CD11c, CD13, CD14, CD15, CD16, CD19, CD20, CD21, CD22, CD23, CD25, CD33, CD34, CD38, CD40, CD40L, CD41a, CD43, CD45, CD55, CD74, TNF-alpha, interferon and HLA-DR.
- Antibodies that bind to these and other target antigens, discussed above, may be used to treat autoimmune or immune dysfunction diseases.
- Autoimmune diseases that may be treated with antibodies or ADCs may include acute idiopathic thrombocytopenic purpura, chronic idiopathic thrombocytopenic purpura, dermatomyositis, Sydenham's chorea, myasthenia gravis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, polyglandular syndromes, bullous pemphigoid, diabetes mellitus, Henoch-Schonlein purpura, post-streptococcal nephritis, erythema nodosum, Takayasu's arteritis, ANCA-associated vasculitides, Addison's disease, rheumatoid arthritis, multiple sclerosis, sarcoidosis, ulcerative co
- CPT-conjugates preferably SN-38-conjugates
- Bispecific antibodies are useful in a number of biomedical applications. For instance, a bispecific antibody with binding sites for a tumor cell surface antigen and for a T-cell surface receptor can direct the lysis of specific tumor cells by T cells. Bispecific antibodies recognizing gliomas and the CD3 epitope on T cells have been successfully used in treating brain tumors in human patients (Nitta, et al. Lancet. 1990; 355:368-371). A preferred bispecific antibody is an anti-CD3 X anti-CD19 antibody.
- an anti-CD3 antibody or fragment thereof may be attached to an antibody or fragment against another B-cell associated antigen, such as anti-CD3 X anti-CD20, anti-CD3 X anti-CD22, anti-CD3 X anti-HLA-DR or anti-CD3 X anti-CD74.
- another B-cell associated antigen such as anti-CD3 X anti-CD20, anti-CD3 X anti-CD22, anti-CD3 X anti-HLA-DR or anti-CD3 X anti-CD74.
- the subject anti-HLA-DR antibody may be utilized in combination with a bispecific antibody as disclosed herein.
- Bispecific antibodies can be produced by the quadroma method, which involves the fusion of two different hybridomas, each producing a monoclonal antibody recognizing a different antigenic site (Milstein and Cuello, Nature, 1983; 305:537-540).
- bispecific antibodies Another method for producing bispecific antibodies uses heterobifunctional cross-linkers to chemically tether two different monoclonal antibodies (Staerz, et al. Nature, 1985; 314:628-631; Perez, et al. Nature, 1985; 316:354-356). Bispecific antibodies can also be produced by reduction of each of two parental monoclonal antibodies to the respective half molecules, which are then mixed and allowed to reoxidize to obtain the hybrid structure (Staerz and Bevan. Proc Natl Acad Sci USA. 1986; 83:1453-1457). Another alternative involves chemically cross-linking two or three separately purified Fab′ fragments using appropriate linkers. (See, e.g., European Patent Application 0453082).
- hybrid hybridomas include improving the efficiency of generating hybrid hybridomas by gene transfer of distinct selectable markers via retrovirus-derived shuttle vectors into respective parental hybridomas, which are fused subsequently (DeMonte, et al. Proc Natl Acad Sci USA. 1990, 87:2941-2945); or transfection of a hybridoma cell line with expression plasmids containing the heavy and light chain genes of a different antibody.
- Cognate V H and V L domains can be joined with a peptide linker of appropriate composition and length (usually consisting of more than 12 amino acid residues) to form a single-chain Fv (scFv) with binding activity.
- a peptide linker of appropriate composition and length usually consisting of more than 12 amino acid residues
- Methods of manufacturing scFvs are disclosed in U.S. Pat. Nos. 4,946,778 and 5,132,405, the Examples section of each of which is incorporated herein by reference. Reduction of the peptide linker length to less than 12 amino acid residues prevents pairing of V H and V L domains on the same chain and forces pairing of V H and V L domains with complementary domains on other chains, resulting in the formation of functional multimers.
- Polypeptide chains of V H and V L domains that are joined with linkers between 3 and 12 amino acid residues form predominantly dimers (termed diabodies). With linkers between 0 and 2 amino acid residues, trimers (termed triabody) and tetramers (termed tetrabody) are favored, but the exact patterns of oligomerization appear to depend on the composition as well as the orientation of V-domains (V H -linker-V L or V L -linker-V H ), in addition to the linker length.
- the technique utilizes complementary protein binding domains, referred to as anchoring domains (AD) and dimerization and docking domains (DDD), which bind to each other and allow the assembly of complex structures, ranging from dimers, trimers, tetramers, quintamers and hexamers. These form stable complexes in high yield without requirement for extensive purification.
- DNL technique allows the assembly of monospecific, bispecific or multispecific antibodies. Any of the techniques known in the art for making bispecific or multispecific antibodies may be utilized in the practice of the presently claimed methods.
- a bispecific or multispecific antibody is formed as a DOCK-AND-LOCK® (DNL®) complex
- DOCK-AND-LOCK® DOCK-AND-LOCK®
- DDD dimerization and docking domain
- R regulatory
- AD anchor domain
- the DDD and AD peptides may be attached to any protein, peptide or other molecule. Because the DDD sequences spontaneously dimerize and bind to the AD sequence, the technique allows the formation of complexes between any selected molecules that may be attached to DDD or AD sequences.
- the standard DNL® complex comprises a trimer with two DDD-linked molecules attached to one AD-linked molecule
- variations in complex structure allow the formation of dimers, trimers, tetramers, pentamers, hexamers and other multimers.
- the DNL® complex may comprise two or more antibodies, antibody fragments or fusion proteins which bind to the same antigenic determinant or to two or more different antigens.
- the DNL® complex may also comprise one or more other effectors, such as proteins, peptides, immunomodulators, cytokines, interleukins, interferons, binding proteins, peptide ligands, carrier proteins, toxins, ribonucleases such as onconase, inhibitory oligonucleotides such as siRNA, antigens or xenoantigens, polymers such as PEG, enzymes, therapeutic agents, hormones, cytotoxic agents, anti-angiogenic agents, pro-apoptotic agents or any other molecule or aggregate.
- effectors such as proteins, peptides, immunomodulators, cytokines, interleukins, interferons, binding proteins, peptide ligands, carrier proteins, toxins, ribonucleases such as onconase, inhibitory oligonucleotides such as siRNA, antigens or xenoantigens, polymers such as PEG, enzymes, therapeutic agents, hormones,
- PKA which plays a central role in one of the best studied signal transduction pathways triggered by the binding of the second messenger cAMP to the R subunits, was first isolated from rabbit skeletal muscle in 1968 (Walsh et al., J. Biol. Chem. 1968; 243:3763).
- the structure of the holoenzyme consists of two catalytic subunits held in an inactive form by the R subunits (Taylor, J. Biol. Chem. 1989; 264:8443). Isozymes of PKA are found with two types of R subunits (RI and RII), and each type has ⁇ and ⁇ isoforms (Scott, Pharmacol. Ther. 1991; 50:123).
- the four isoforms of PKA regulatory subunits are RI ⁇ , RI ⁇ , RII ⁇ and RII ⁇ .
- the R subunits have been isolated only as stable dimers and the dimerization domain has been shown to consist of the first 44 amino-terminal residues of RII ⁇ (Newlon et al., Nat. Struct. Biol. 1999; 6:222).
- similar portions of the amino acid sequences of other regulatory subunits are involved in dimerization and docking, each located near the N-terminal end of the regulatory subunit.
- Binding of cAMP to the R subunits leads to the release of active catalytic subunits for a broad spectrum of serine/threonine kinase activities, which are oriented toward selected substrates through the compartmentalization of PKA via its docking with AKAPs (Scott et al., J. Biol. Chem. 1990; 265; 21561)
- AKAP microtubule-associated protein-2
- the amino acid sequences of the AD are quite varied among individual AKAPs, with the binding affinities reported for Ril dimers ranging from 2 to 90 nM (Alto et al., Proc. Natl. Acad. Sci. USA. 2003; 100:4445). AKAPs will only bind to dimeric R subunits.
- human RIIcc the AD binds to a hydrophobic surface formed by the 23 amino-terminal residues (Colledge and Scott, Trends Cell Biol. 1999; 6:216).
- the dimerization domain and AKAP binding domain of human RII ⁇ are both located within the same N-terminal 44 amino acid sequence (Newlon et al., Nat. Struct. Biol. 1999; 6:222; Newlon et al., EMBO J. 2001; 20:1651), which is termed the DDD herein.
- Entity A is constructed by linking a DDD sequence to a precursor of A, resulting in a first component hereafter referred to as a. Because the DDD sequence would effect the spontaneous formation of a dimer, A would thus be composed of a 2 .
- Entity B is constructed by linking an AD sequence to a precursor of B, resulting in a second component hereafter referred to as b.
- the dimeric motif of DDD contained in a 2 will create a docking site for binding to the AD sequence contained in b, thus facilitating a ready association of a 2 and b to form a binary, trimeric complex composed of a 2 b.
- This binding event is made irreversible with a subsequent reaction to covalently secure the two entities via disulfide bridges, which occurs very efficiently based on the principle of effective local concentration because the initial binding interactions should bring the reactive thiol groups placed onto both the DDD and AD into proximity (Chmura et al., Proc. Natl. Acad. Sci. USA.
- fusion proteins A variety of methods are known for making fusion proteins, including nucleic acid synthesis, hybridization and/or amplification to produce a synthetic double-stranded nucleic acid encoding a fusion protein of interest.
- double-stranded nucleic acids may be inserted into expression vectors for fusion protein production by standard molecular biology techniques (see, e.g. Sambrook et al., Molecular Cloning, A laboratory manual, 2 nd Ed, 1989).
- the AD and/or DDD moiety may be attached to either the N-terminal or C-terminal end of an effector protein or peptide.
- site of attachment of an AD or DDD moiety to an effector moiety may vary, depending on the chemical nature of the effector moiety and the part(s) of the effector moiety involved in its physiological activity.
- Site-specific attachment of a variety of effector moieties may be performed using techniques known in the art, such as the use of bivalent cross-linking reagents and/or other chemical conjugation techniques.
- an antibody or antibody fragment may be incorporated into a DNL® complex by, for example, attaching a DDD or AD moiety to the C-terminal end of the antibody heavy chain, as described in detail below.
- the DDD or AD moiety more preferably the AD moiety, may be attached to the C-terminal end of the antibody light chain (see, e.g., U.S. patent application Ser. No. 13/901,737, filed May 24, 2013, the Examples section of which is incorporated herein by reference.)
- Immunogenicity of therapeutic antibodies is associated with increased risk of infusion reactions and decreased duration of therapeutic response (Baert et al., 2003, N Engl J Med 348:602-08).
- the extent to which therapeutic antibodies induce an immune response in the host may be determined in part by the allotype of the antibody (Stickler et al., 2011, Genes and Immunity 12:213-21).
- Antibody allotype is related to amino acid sequence variations at specific locations in the constant region sequences of the antibody.
- the allotypes of IgG antibodies containing a heavy chain ⁇ -type constant region are designated as Gm allotypes (1976, J Immunol 117:1056-59).
- G1m1 For the common IgG1 human antibodies, the most prevalent allotype is G1m1 (Stickler et al., 2011, Genes and Immunity 12:213-21). However, the G1m3 allotype also occurs frequently in Caucasians (Id.). It has been reported that G1m1 antibodies contain allotypic sequences that tend to induce an immune response when administered to non-G1m1 (nG1m1) recipients, such as G1m3 patients (Id.). Non-G1m1 allotype antibodies are not as immunogenic when administered to G1m1 patients (Id.).
- the human G1m1 allotype comprises the amino acids aspartic acid at Kabat position 356 and leucine at Kabat position 358 in the CH3 sequence of the heavy chain IgG1.
- the nG1m1 allotype comprises the amino acids glutamic acid at Kabat position 356 and methionine at Kabat position 358.
- Both G1m1 and nG1m1 allotypes comprise a glutamic acid residue at Kabat position 357 and the allotypes are sometimes referred to as DEL and EEM allotypes.
- a non-limiting example of the heavy chain constant region sequences for G1m1 and nG1m1 allotype antibodies is shown for the exemplary antibodies rituximab (SEQ ID NO:7) and veltuzumab (SEQ ID NO:8).
- veltuzumab and rituximab are, respectively, humanized and chimeric IgG1 antibodies against CD20, of use for therapy of a wide variety of hematological malignancies.
- Table 1 compares the allotype sequences of rituximab vs. veltuzumab.
- rituximab (G1m17,1) is a DEL allotype IgG1, with an additional sequence variation at Kabat position 214 (heavy chain CH1) of lysine in rituximab vs. arginine in veltuzumab.
- veltuzumab is less immunogenic in subjects than rituximab (see, e.g., Morchhauser et al., 2009, J Clin Oncol 27:3346-53; Goldenberg et al., 2009, Blood 113:1062-70; Robak & Robak, 2011, BioDrugs 25:13-25), an effect that has been attributed to the difference between humanized and chimeric antibodies.
- the difference in allotypes between the EEM and DEL allotypes likely also accounts for the lower immunogenicity of veltuzumab.
- the allotype of the antibody In order to reduce the immunogenicity of therapeutic antibodies in individuals of nG1m1 genotype, it is desirable to select the allotype of the antibody to correspond to the G1m3 allotype, characterized by arginine at Kabat 214, and the nG1m1,2 null-allotype, characterized by glutamic acid at Kabat position 356, methionine at Kabat position 358 and alanine at Kabat position 431. Surprisingly, it was found that repeated subcutaneous administration of G1m3 antibodies over a long period of time did not result in a significant immune response.
- the human IgG4 heavy chain in common with the G1m3 allotype has arginine at Kabat 214, glutamic acid at Kabat 356, methionine at Kabat 359 and alanine at Kabat 431. Since immunogenicity appears to relate at least in part to the residues at those locations, use of the human IgG4 heavy chain constant region sequence for therapeutic antibodies is also a preferred embodiment. Combinations of G1m3 IgG1 antibodies with IgG4 antibodies may also be of use for therapeutic administration.
- the disclosed methods and compositions may involve production and use of proteins or peptides with one or more substituted amino acid residues.
- the DDD and/or AD sequences used to make DNL® constructs may be modified as discussed above.
- amino acid substitutions typically involve the replacement of an amino acid with another amino acid of relatively similar properties (i.e., conservative amino acid substitutions).
- conservative amino acid substitutions The properties of the various amino acids and effect of amino acid substitution on protein structure and function have been the subject of extensive study and knowledge in the art.
- the hydropathic index of amino acids may be considered (Kyte & Doolittle, 1982, J. Mol. Biol., 157:105-132).
- the relative hydropathic character of the amino acid contributes to the secondary structure of the resultant protein, which in turn defines the interaction of the protein with other molecules.
- Each amino acid has been assigned a hydropathic index on the basis of its hydrophobicity and charge characteristics (Kyte & Doolittle, 1982), these are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine/cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine ( ⁇ 0.4); threonine ( ⁇ 0.7); serine ( ⁇ 0.8); tryptophan ( ⁇ 0.9); tyrosine ( ⁇ 1.3); proline ( ⁇ 1.6); histidine ( ⁇ 3.2); glutamate ( ⁇ 3.5); glutamine ( ⁇ 3.5); aspartate ( ⁇ 3.5); asparagine ( ⁇ 3.5); lysine ( ⁇ 3.9); and arginine ( ⁇ 4.5).
- the use of amino acids whose hydropathic indices are within ⁇ 2 is preferred, within ⁇ 1 are more preferred, and within ⁇ 0.5 are even more preferred.
- Amino acid substitution may also take into account the hydrophilicity of the amino acid residue (e.g., U.S. Pat. No. 4,554,101). Hydrophilicity values have been assigned to amino acid residues: arginine (+3.0); lysine (+3.0); aspartate (+3.0); glutamate (+3.0); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine ( ⁇ 0.4); proline ( ⁇ 0.5.+ ⁇ .1); alanine ( ⁇ 0.5); histidine ( ⁇ 0.5); cysteine ( ⁇ 1.0); methionine ( ⁇ 1.3); valine ( ⁇ 1.5); leucine ( ⁇ 1.8); isoleucine ( ⁇ 1.8); tyrosine ( ⁇ 2.3); phenylalanine ( ⁇ 2.5); tryptophan ( ⁇ 3.4). Replacement of amino acids with others of similar hydrophilicity is preferred.
- amino acid side chain For example, it would generally not be preferred to replace an amino acid with a compact side chain, such as glycine or serine, with an amino acid with a bulky side chain, e.g., tryptophan or tyrosine.
- a compact side chain such as glycine or serine
- an amino acid with a bulky side chain e.g., tryptophan or tyrosine.
- the effect of various amino acid residues on protein secondary structure is also a consideration. Through empirical study, the effect of different amino acid residues on the tendency of protein domains to adopt an alpha-helical, beta-sheet or reverse turn secondary structure has been determined and is known in the art (see, e.g., Chou & Fasman, 1974, Biochemistry, 13:222-245; 1978, Ann. Rev. Biochem., 47: 251-276; 1979, Biophys. J., 26:367-384).
- amino acid substitutions include whether or not the residue is located in the interior of a protein or is solvent exposed.
- conservative substitutions would include: Asp and Asn; Ser and Thr; Ser and Ala; Thr and Ala; Ala and Gly; Ile and Val; Val and Leu; Leu and Ile; Leu and Met; Phe and Tyr; Tyr and Trp.
- conservative substitutions would include: Asp and Asn; Asp and Glu; Glu and Gln; Glu and Ala; Gly and Asn; Ala and Pro; Ala and Gly; Ala and Ser; Ala and Lys; Ser and Thr; Lys and Arg; Val and Leu; Leu and Ile; Ile and Val; Phe and Tyr.
- amino acid substitutions In determining amino acid substitutions, one may also consider the existence of intermolecular or intramolecular bonds, such as formation of ionic bonds (salt bridges) between positively charged residues (e.g., His, Arg, Lys) and negatively charged residues (e.g., Asp, Glu) or disulfide bonds between nearby cysteine residues.
- ionic bonds salt bridges
- positively charged residues e.g., His, Arg, Lys
- negatively charged residues e.g., Asp, Glu
- disulfide bonds between nearby cysteine residues.
- the preferred conjugation protocol is based on a thiol-maleimide, a thiol-vinylsulfone, a thiol-bromoacetamide, or a thiol-iodoacetamide reaction that is facile at neutral or acidic pH. This obviates the need for higher pH conditions for conjugations as, for instance, would be necessitated when using active esters. Further details of exemplary conjugation protocols are described below in the Examples section.
- the invention in another aspect, relates to a method of treating a subject, preferably a human subject, comprising administering a therapeutically effective amount of an antibody or ADC as described herein to a subject, preferably in combination with a Bruton's kinase inhibitor and/or PI3K inhibitor.
- B-cell malignancies e.g., non-Hodgkin's lymphoma, mantle cell lymphoma, multiple myeloma, Hodgkin's lymphoma, diffuse large B cell lymphoma, Burkitt lymphoma, follicular lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia
- an anti-HLA-DR antibody such as the IMMU-114.
- Other diseases include, but are not limited to, cancers of the skin, esophagus, stomach, colon, rectum, pancreas, lung, breast, ovary, bladder, endometrium, cervix, testes, kidney, liver, melanoma or other HLA-DR-producing tumors.
- cancers of the skin, esophagus, stomach, colon, rectum, pancreas, lung, breast, ovary, bladder, endometrium, cervix, testes, kidney, liver, melanoma or other HLA-DR-producing tumors In alternative embodiments involving treatment with an antibody binding to a TAA other than HLA-DR, the person of ordinary skill will realize that different types of cancer that are known to express the TAA may be treated.
- Such therapeutics can be given once or repeatedly, depending on the disease state and tolerability of the conjugate, and can also be used optionally in combination with other therapeutic modalities, such as surgery, external radiation, radioimmunotherapy, immunotherapy, chemotherapy, antisense therapy, interference RNA therapy, gene therapy, and the like. Each combination will be adapted to the tumor type, stage, patient condition and prior therapy, and other factors considered by the managing physician.
- the term “subject” refers to any animal (i.e., vertebrates and invertebrates) including, but not limited to mammals, including humans. It is not intended that the term be limited to a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are encompassed by the term. Doses given herein are for humans, but can be adjusted to the size of other mammals, as well as children, in accordance with weight or square meter size. Where an antibody or ADC is administered to a human subject, the person of ordinary skill will realize that the target antigen to which the antibody or ADC binds will be a human antigen.
- antibodies or ADCs comprising an anti-HLA-DR MAb can be used to treat lymphoma, leukemia, multiple myeloma, cancers of the skin, esophagus, stomach, colon, rectum, pancreas, lung, breast, ovary, bladder, endometrium, cervix, testes, kidney, liver, melanoma or other HLA-DR-producing tumors, as disclosed in U.S. Pat. No. 7,612,180, the Examples section of which is incorporated herein by reference.
- An hL243 antibody is a humanized antibody comprising the heavy chain CDR sequences CDR1 (NYGMN, SEQ ID NO:1), CDR2 (WINTYTREPTYADDFKG, SEQ ID NO:2), and CDR3 (DITAVVPTGFDY, SEQ ID NO:3) and light chain CDR sequences CDR1 (RASENIYSNLA, SEQ ID NO:4), CDR2 (AASNLAD, SEQ ID NO:5), and CDR3 (QHFWTTPWA, SEQ ID NO:6).
- the antibodies or ADCs can be used to treat autoimmune disease or immune system dysfunction (e.g., graft-versus-host disease, organ transplant rejection).
- Antibodies of use to treat autoimmune/immune dysfunction disease may bind to exemplary antigens including, but not limited to, BCL-1, BCL-2, BCL-6, CD1a, CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD11b, CD11c, CD13, CD14, CD15, CD16, CD19, CD20, CD21, CD22, CD23, CD25, CD33, CD34, CD38, CD40, CD40L, CD41a, CD43, CD45, CD55, CD56, CCD57, CD59, CD64, CD71, CD74, CD79a, CD79b, CD117, CD138, FMC-7 and HLA-DR.
- Antibodies that bind to these and other target antigens, discussed above, may be used to treat autoimmune or immune dysfunction diseases.
- Autoimmune diseases that may be treated with antibodies or ADCs may include acute idiopathic thrombocytopenic purpura, chronic idiopathic thrombocytopenic purpura, dermatomyositis, Sydenham's chorea, myasthenia gravis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, polyglandular syndromes, bullous pemphigoid, diabetes mellitus, Henoch-Schonlein purpura, post-streptococcal nephritis, erythema nodosum, Takayasu's arteritis, ANCA-associated vasculitides, Addison's disease, rheumatoid arthritis, multiple sclerosis, sarcoidosis, ulcerative co
- a therapeutic agent used in combination with the subject antibodies may comprise one or more isotopes.
- Radioactive isotopes useful for treating diseased tissue include, but are not limited to— 111 In, 177 Lu, 212 Bi, 213 Bi, 211 At, 62 Cu, 67 Cu, 90 Y, 125 I, 131 I, 32 P, 33 P, 47 Sc, 111 Ag, 67 Ga, 142 Pr, 153 Sm, 161 Tb, 166 Dy, 166 Ho, 186 Re, 188 Re, 189 Re, 212 Pb, 223 Ra, 225 Ac, 59 Fe, 75 Se, 77 As, 89 Sr, 99 Mo, 105 Rh, 109 Pd, 143 Pr, 149 Pm, 169 Er, 194 Ir, 198 Au, 199 Au, 227 Th and 211 Pb.
- the therapeutic radionuclide preferably has a decay-energy in the range of 20 to 6,000 keV, preferably in the ranges 60 to 200 keV for an Auger emitter, 100-2,500 keV for a beta emitter, and 4,000-6,000 keV for an alpha emitter.
- Maximum decay energies of useful beta-particle-emitting nuclides are preferably 20-5,000 keV, more preferably 100-4,000 keV, and most preferably 500-2,500 keV. Also preferred are radionuclides that substantially decay with Auger-emitting particles.
- beta-particle-emitting nuclides are preferably ⁇ 1,000 keV, more preferably ⁇ 100 keV, and most preferably ⁇ 70 keV. Also preferred are radionuclides that substantially decay with generation of alpha-particles.
- Such radionuclides include, but are not limited to: Dy-152, At-211, Bi-212, Ra-223, Rn-219, Po-215, Bi-211, Ac-225, Fr-221, At-217, Bi-213, Th-227 and Fm-255. Decay energies of useful alpha-particle-emitting radionuclides are preferably 2,000-10,000 keV, more preferably 3,000-8,000 keV, and most preferably 4,000-7,000 keV.
- radioisotopes of use include 11 C, 13 N, 15 O, 75 Br, 198 Au, 224 Ac, 126 I, 13 I, 77 Br, 113m In, 95 Ru, 97 Ru, 103 Ru, 105 Ru, 107 Hg, 203 Hg, 121m Te, 122m Te, 125m Te, 165 Tm, 167 Tm, 168 Tm, 197 Pt, 109 Pd, 105 Rh, 142 Pr, 143 Pr, 161 Tb, 166 Ho, 199 Au, 57 Co, 58 Co, 51 Cr, 59 Fe, 75 Se, 201 Tl, 225 Ac, 76 Br, 169 Yb, and the like.
- Radionuclides and other metals may be delivered, for example, using chelating groups attached to an antibody or ADC.
- Macrocyclic chelates such as NOTA, DOTA, and TETA are of use with a variety of metals and radiometals, most particularly with radionuclides of gallium, yttrium and copper, respectively.
- metal-chelate complexes can be made very stable by tailoring the ring size to the metal of interest.
- Other ring-type chelates, such as macrocyclic polyethers for complexing 223 Ra may be used.
- Therapeutic agents of use in combination with the antibodies or ADCs described herein also include, for example, chemotherapeutic drugs such as vinca alkaloids, anthracyclines, epidophyllotoxins, taxanes, antimetabolites, tyrosine kinase inhibitors, alkylating agents, antibiotics, Cox-2 inhibitors, antimitotics, antiangiogenic and proapoptotic agents, particularly doxorubicin, methotrexate, taxol, other camptothecins, and others from these and other classes of anticancer agents, and the like.
- chemotherapeutic drugs such as vinca alkaloids, anthracyclines, epidophyllotoxins, taxanes, antimetabolites, tyrosine kinase inhibitors, alkylating agents, antibiotics, Cox-2 inhibitors, antimitotics, antiangiogenic and proapoptotic agents, particularly doxorubicin, methotrexate, taxol, other camptothec
- cancer chemotherapeutic drugs include nitrogen mustards, alkyl sulfonates, nitrosoureas, triazenes, folic acid antagonists, pyrimidine analogs, purine analogs, platinum coordination complexes, hormones, and the like.
- Suitable chemotherapeutic agents are described in REMINGTON'S PHARMACEUTICAL SCIENCES, 19th Ed. (Mack Publishing Co. 1995), and in GOODMAN AND GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 7th Ed. (MacMillan Publishing Co. 1985), as well as revised editions of these publications.
- Other suitable chemotherapeutic agents, such as experimental drugs are known to those of skill in the art.
- Exemplary drugs of use include, but are not limited to, 5-fluorouracil, afatinib, aplidin, azaribine, anastrozole, anthracyclines, axitinib, AVL-101, AVL-291, bendamustine, bleomycin, bortezomib, bosutinib, bryostatin-1, busulfan, calicheamycin, camptothecin, carboplatin, 10-hydroxycamptothecin, carmustine, celebrex, chlorambucil, cisplatin (CDDP), Cox-2 inhibitors, irinotecan (CPT-11), SN-38, carboplatin, cladribine, camptothecans, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dasatinib, dinaciclib, docetaxel, dactinomycin, daunorubicin, doxor
- Such agents may be part of the conjugates described herein or may alternatively be administered in combination with the disclosed antibodies or ADCs, either prior to, simultaneously with or after the antibody or ADC.
- one or more therapeutic naked antibodies as are known in the art may be used in combination with the disclosed antibodies or ADCs. Exemplary therapeutic naked antibodies are described above.
- a therapeutic agent to be used in combination an antibody or ADC and/or a Bruton's kinase or PI3K inhibitor may be a microtubule inhibitor, such as a vinca alkaloid, a taxanes, a maytansinoid or an auristatin.
- Exemplary known microtubule inhibitors include paclitaxel, vincristine, vinblastine, mertansine, epothilone, docetaxel, discodermolide, combrestatin, podophyllotoxin, CI-980, phenylahistins, steganacins, curacins, 2-methoxy estradiol, E7010, methoxy benzenesuflonamides, vinorelbine, vinflunine, vindesine, dolastatins, spongistatin, rhizoxin, tasidotin, halichondrins, hemiasterlins, cryptophycin 52, MMAE and eribulin mesylate.
- a therapeutic agent to be used in combination with an antibody or ADC and/or a Bruton's kinase or PI3K inhibitor is a PARP inhibitor, such as olaparib, talazoparib (BMN-673), rucaparib, veliparib, CEP 9722, MK 4827, BGB-290, ABT-888, AG014699, BSI-201, CEP-8983 or 3-aminobenzamide.
- a PARP inhibitor such as olaparib, talazoparib (BMN-673), rucaparib, veliparib, CEP 9722, MK 4827, BGB-290, ABT-888, AG014699, BSI-201, CEP-8983 or 3-aminobenzamide.
- Bruton's kinase inhibitors include, but are not limited to, ibrutinib (PCI-32765), PCI-45292, CC-292 (AVL-292), ONO-4059, GDC-0834, LFM-A13 or RN486.
- PI3K inhibitors include, but are not limited to, idelalisib, Wortmannin, demethoxyviridin, perifosine, PX-866, IPI-145 (duvelisib), BAY 80-6946, BEZ235, RP6530, TGR1202, SF1126, INK1117, GDC-0941, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115, CAL263, PI-103, GNE477, CUDC-907, AEZS-136 or LY294002.
- Therapeutic agents that may be used in concert with the antibodies or ADCs also may comprise toxins conjugated to targeting moieties.
- Toxins that may be used in this regard include ricin, abrin, ribonuclease (RNase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin, and Pseudomonas endotoxin.
- RNase ribonuclease
- DNase I DNase I
- Staphylococcal enterotoxin-A Staphylococcal enterotoxin-A
- pokeweed antiviral protein pokeweed antiviral protein
- gelonin gelonin
- diphtheria toxin diphtheria toxin
- Pseudomonas exotoxin Pseudomonas endotoxin.
- Additional toxins suitable for use herein are
- Immunomodulators of use may be selected from a cytokine, a stem cell growth factor, a lymphotoxin, an hematopoietic factor, a colony stimulating factor (CSF), an interferon (IFN), erythropoietin, thrombopoietin and a combination thereof.
- CSF colony stimulating factor
- IFN interferon
- lymphotoxins such as tumor necrosis factor (TNF), hematopoietic factors, such as interleukin (IL), colony stimulating factor, such as granulocyte-colony stimulating factor (G-CSF) or granulocyte macrophage-colony stimulating factor (GM-CSF), interferon, such as interferons- ⁇ , - ⁇ , - ⁇ or - ⁇ , and stem cell growth factor, such as that designated “S1 factor”.
- TNF tumor necrosis factor
- IL interleukin
- colony stimulating factor such as granulocyte-colony stimulating factor (G-CSF) or granulocyte macrophage-colony stimulating factor (GM-CSF)
- interferon such as interferons- ⁇ , - ⁇ , - ⁇ or - ⁇
- stem cell growth factor such as that designated “S1 factor”.
- cytokines include growth hormones such as human growth hormone, N-methionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH); hepatic growth factor; prostaglandin, fibroblast growth factor; prolactin; placental lactogen, OB protein; tumor necrosis factor- ⁇ and -ß; mullerian-inhibiting substance; mouse gonadotropin-associated peptide; inhibin; activin; vascular endothelial growth factor; integrin; thrombopoietin (TPO); nerve growth factors such as NGF-ß; platelet-growth factor; transforming growth factors (TGFs) such as TGF- ⁇ and TGF-ß; insulin-like growth factor-I and -II; erythropoietin (
- Chemokines of use include RANTES, MCAF, MIP1-alpha, MIP1-Beta and IP-10.
- the subject antibodies or ADCs may be used alone or in combination with one or more other therapeutic agents, such as a second antibody, second antibody fragment, second ADC, radionuclide, toxin, drug, chemotherapeutic agent, radiation therapy, chemokine, cytokine, immunomodulator, enzyme, hormone, oligonucleotide, RNAi or siRNA.
- the therapeutic agent is a Bruton's kinase inhibitor or a PI3K inhibitor.
- Suitable routes of administration of the antibodies, ADCs and/or kinase inhibitors include, without limitation, parenteral, subcutaneous, rectal, transmucosal, intestinal administration, intramuscular, intramedullary, intrathecal, direct intraventricular, intravenous, intravitreal, intraperitoneal, intranasal, or intraocular injections.
- the preferred routes of administration are parenteral.
- Certain therapeutic agents such as microtubule inhibitors, PARP inhibitors, Bruton's kinase inhibitors or PI3K inhibitors may be designed to be administered orally.
- Antibodies or ADCs can be formulated according to known methods to prepare pharmaceutically useful compositions, whereby the antibody or ADC is combined in a mixture with a pharmaceutically suitable excipient.
- Sterile phosphate-buffered saline is one example of a pharmaceutically suitable excipient.
- Other suitable excipients are well-known to those in the art. See, for example, Ansel et al., PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS, 5th Edition (Lea & Febiger 1990), and Gennaro (ed.), REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Edition (Mack Publishing Company 1990), and revised editions thereof.
- the antibody or ADC is formulated in Good's biological buffer (pH 6-7), using a buffer selected from the group consisting of N-(2-acetamido)-2-aminoethanesulfonic acid (ACES); N-(2-acetamido)iminodiacetic acid (ADA); N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES); 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES); 2-(N-morpholino)ethanesulfonic acid (MES); 3-(N-morpholino)propanesulfonic acid (MOPS); 3-(N-morpholinyl)-2-hydroxypropanesulfonic acid (MOPSO); and piperazine-N,N′-bis(2-ethanesulfonic acid) [Pipes].
- a buffer selected from the group consisting of N-(2-acetamido)-2-aminoethane
- More preferred buffers are MES or MOPS, preferably in the concentration range of 20 to 100 mM, more preferably about 25 mM. Most preferred is 25 mM MES, pH 6.5.
- the formulation may further comprise 25 mM trehalose and 0.01% v/v polysorbate 80 as excipients, with the final buffer concentration modified to 22.25 mM as a result of added excipients.
- the preferred method of storage is as a lyophilized formulation of the conjugates, stored in the temperature range of ⁇ 20° C. to 2° C., with the most preferred storage at 2° C. to 8° C.
- the antibody or ADC can be formulated for intravenous administration via, for example, bolus injection, slow infusion or continuous infusion.
- the antibody of the present invention is infused over a period of less than about 4 hours, and more preferably, over a period of less than about 3 hours.
- the first 25-50 mg could be infused within 30 minutes, preferably even 15 min, and the remainder infused over the next 2-3 hrs.
- Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
- the compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
- an antibody or ADC may be administered by subcutaneous injection, either as a primary treatment or for maintenance therapy following, e.g., intravenous administration of the antibody or ADC.
- Control release preparations can be prepared through the use of polymers to complex or adsorb the ADC.
- biocompatible polymers include matrices of poly(ethylene-co-vinyl acetate) and matrices of a polyanhydride copolymer of a stearic acid dimer and sebacic acid. Sherwood et al., Bio/Technology 10: 1446 (1992). The rate of release of an antibody or ADC from such a matrix depends upon the molecular weight, the amount of antibody or ADC within the matrix, and the size of dispersed particles. Saltzman et al., Biophys. J.
- the dosage of an administered antibody or ADC for humans will vary depending upon such factors as the patient's age, weight, height, sex, general medical condition and previous medical history. It may be desirable to provide the recipient with a dosage of ADC that is in the range of from about 1 mg/kg to 24 mg/kg, more preferably 4 to 16 mg/kg, more preferably 8 to 10 mg/kg, as a single intravenous infusion, although a lower or higher dosage also may be administered as circumstances dictate.
- a dosage of 1-20 mg/kg for a 70 kg patient for example, is 70-1,400 mg, or 41-824 mg/m 2 for a 1.7-m patient.
- the dosage may be repeated as needed, for example, once per week for 4-10 weeks, once per week for 8 weeks, or once per week for 4 weeks. It may also be given less frequently, such as every other week for several months, or monthly or quarterly for many months, as needed in a maintenance therapy.
- Preferred dosages may include, but are not limited to, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg, 22 mg/kg and 24 mg/kg.
- preferred dosages would be in the range of 1.5 to 4.0 mg/kg.
- a subcutaneous dosage may be administered at a single site, or may alternatively be administered at multiple sites, each of which may receive a dosage of 1.5 to 4.0 mg/kg.
- an initial treatment of ADC administered intravenously may be followed by a maintenance dosage administered subcutaneously.
- the dosage is preferably administered multiple times, once or twice a week, or as infrequently as once every 3 or 4 weeks.
- a minimum dosage schedule of 4 weeks, more preferably 8 weeks, more preferably 16 weeks or longer may be used.
- the schedule of administration may comprise administration once or twice a week, on a cycle selected from the group consisting of: (i) weekly; (ii) every other week; (iii) one week of therapy followed by two, three or four weeks off; (iv) two weeks of therapy followed by one, two, three or four weeks off; (v) three weeks of therapy followed by one, two, three, four or five week off; (vi) four weeks of therapy followed by one, two, three, four or five week off; (vii) five weeks of therapy followed by one, two, three, four or five week off; (viii) monthly and (ix) every 3 weeks.
- the cycle may be repeated 2, 4, 6, 8, 10, 12, 16 or 20 times or more.
- an antibody or ADC may be administered as one dosage every 2 or 3 weeks, repeated for a total of at least 3 dosages. Or, twice per week for 4-6 weeks. If the dosage is lowered to approximately 200-300 mg/m 2 (340 mg per dosage for a 1.7-m patient, or 4.9 mg/kg for a 70 kg patient), it may be administered once or even twice weekly for 4 to 10 weeks. Alternatively, the dosage schedule may be decreased, namely every 2 or 3 weeks for 2-3 months. It has been determined, however, that even higher doses, such as 12 mg/kg once weekly or once every 2-3 weeks can be administered by slow i.v. infusion, for repeated dosing cycles. The dosing schedule can optionally be repeated at other intervals and dosage may be given through various parenteral routes, with appropriate adjustment of the dose and schedule.
- the antibodies or ADCs are of use for therapy of cancer.
- cancers include, but are not limited to, carcinoma, lymphoma, glioblastoma, melanoma, sarcoma, and leukemia, myeloma, or lymphoid malignancies.
- squamous cell cancer e.g., epithelial squamous cell cancer
- Ewing sarcoma e.g., Ewing sarcoma
- Wilms tumor astrocytomas
- glioblastomas lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma multiforme, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, hepatocellular carcinoma, neuroendocrine tumors, medullary thyroid cancer, differentiated thyroid carcinoma, breast cancer, ovarian cancer, colon cancer, rectal cancer, endometrial cancer or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulvar cancer, anal carcinoma, penile carcinoma, as well as head-and-neck cancer.
- squamous cell cancer
- cancer includes primary malignant cells or tumors (e.g., those whose cells have not migrated to sites in the subject's body other than the site of the original malignancy or tumor) and secondary malignant cells or tumors (e.g., those arising from metastasis, the migration of malignant cells or tumor cells to secondary sites that are different from the site of the original tumor).
- primary malignant cells or tumors e.g., those whose cells have not migrated to sites in the subject's body other than the site of the original malignancy or tumor
- secondary malignant cells or tumors e.g., those arising from metastasis, the migration of malignant cells or tumor cells to secondary sites that are different from the site of the original tumor.
- cancers or malignancies include, but are not limited to: Acute Childhood Lymphoblastic Leukemia, Acute Lymphoblastic Leukemia, Acute Lymphocytic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, Adult (Primary) Hepatocellular Cancer, Adult (Primary) Liver Cancer, Adult Acute Lymphocytic Leukemia, Adult Acute Myeloid Leukemia, Adult Hodgkin's Lymphoma, Adult Lymphocytic Leukemia, Adult Non-Hodgkin's Lymphoma, Adult Primary Liver Cancer, Adult Soft Tissue Sarcoma, AIDS-Related Lymphoma, AIDS-Related Malignancies, Anal Cancer, Astrocytoma, Bile Duct Cancer, Bladder Cancer, Bone Cancer, Brain Stem Glioma, Brain Tumors, Breast Cancer, Cancer of the Renal Pelvis and Ureter, Central Nervous System (Primary) Lymphoma,
- compositions described and claimed herein may be used to treat malignant or premalignant conditions and to prevent progression to a neoplastic or malignant state, including but not limited to those disorders described above.
- Such uses are indicated in conditions known or suspected of preceding progression to neoplasia or cancer, in particular, where non-neoplastic cell growth consisting of hyperplasia, metaplasia, or most particularly, dysplasia has occurred (for review of such abnormal growth conditions, see Robbins and Angell, Basic Pathology, 2d Ed., W. B. Saunders Co., Philadelphia, pp. 68-79 (1976)).
- Dysplasia is frequently a forerunner of cancer, and is found mainly in the epithelia. It is the most disorderly form of non-neoplastic cell growth, involving a loss in individual cell uniformity and in the architectural orientation of cells. Dysplasia characteristically occurs where there exists chronic irritation or inflammation.
- Dysplastic disorders which can be treated include, but are not limited to, anhidrotic ectodermal dysplasia, anterofacial dysplasia, asphyxiating thoracic dysplasia, atriodigital dysplasia, bronchopulmonary dysplasia, cerebral dysplasia, cervical dysplasia, chondroectodermal dysplasia, cleidocranial dysplasia, congenital ectodermal dysplasia, craniodiaphysial dysplasia, craniocarpotarsal dysplasia, craniometaphysial dysplasia, dentin dysplasia, diaphysial dysplasia, ectodermal dysplasia, enamel dysplasia, encephalo-ophthalmic dysplasia, dysplasia epiphysialis hemimelia, dysplasia epiphysialis multiplex, dysplasia epiphysialis punctata, epi
- Additional pre-neoplastic disorders which can be treated include, but are not limited to, benign dysproliferative disorders (e.g., benign tumors, fibrocystic conditions, tissue hypertrophy, intestinal polyps or adenomas, and esophageal dysplasia), leukoplakia, keratoses, Bowen's disease, Farmer's Skin, solar cheilitis, and solar keratosis.
- benign dysproliferative disorders e.g., benign tumors, fibrocystic conditions, tissue hypertrophy, intestinal polyps or adenomas, and esophageal dysplasia
- leukoplakia keratoses
- Bowen's disease keratoses
- Farmer's Skin Farmer's Skin
- solar cheilitis solar cheilitis
- the method of the invention is used to inhibit growth, progression, and/or metastasis of cancers, in particular those listed above.
- Additional hyperproliferative diseases, disorders, and/or conditions include, but are not limited to, progression, and/or metastases of malignancies and related disorders such as leukemia (including acute leukemias; e.g., acute lymphocytic leukemia, acute myelocytic leukemia [including myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia]) and chronic leukemias (e.g., chronic myelocytic [granulocytic] leukemia and chronic lymphocytic leukemia), polycythemia vera, lymphomas (e.g., Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenström's macroglobulinemia, heavy chain disease, and solid tumors including, but not limited to, sarcomas and carcinomas such as fibrosarcoma, myxosarcoma, liposarcoma
- Autoimmune diseases that may be treated with antibodies or ADCs may include acute and chronic immune thrombocytopenias, dermatomyositis, Sydenham's chorea, myasthenia gravis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, polyglandular syndromes, bullous pemphigoid, diabetes mellitus, Henoch-Schonlein purpura, post-streptococcal nephritis, erythema nodosum, Takayasu's arteritis, ANCA-associated vasculitides, Addison's disease, rheumatoid arthritis, multiple sclerosis, sarcoidosis, ulcerative colitis, erythema multiforme, IgA nephropathy, polyarteritis nodosa, ankylosing spondylitis, Goodpasture's syndrome, thromboang
- kits containing components suitable for treating diseased tissue in a patient.
- Exemplary kits may contain at least one antibody or ADC as described herein.
- a kit may also include a kinase inhibitor selected from Bruton's kinase inhibitors and/or PI3K inhibitors.
- a device capable of delivering the kit components through some other route may be included.
- One type of device, for applications such as parenteral delivery, is a syringe that is used to inject the composition into the body of a subject. Inhalation devices may also be used.
- the kit components may be packaged together or separated into two or more containers.
- the containers may be vials that contain sterile, lyophilized formulations of a composition that are suitable for reconstitution.
- a kit may also contain one or more buffers suitable for reconstitution and/or dilution of other reagents.
- Other containers that may be used include, but are not limited to, a pouch, tray, box, tube, or the like.
- Kit components may be packaged and maintained sterilely within the containers. Another component that can be included is instructions to a person using a kit for its use.
- IMMU-114 is a humanized anti-HLA-DR IgG 4 monoclonal antibody currently under investigation for non-Hodgkin's lymphoma and CLL (ClinicalTrials.gov, NCT01728207).
- the present Example compared IMMU-114 efficacy to anti-CD20 or doxorubicin therapy, respectively, as well in combination with Bruton's tyrosine kinase (Btk) or phosphoinositide-3-kinase (PI3K) inhibitors.
- Btk Bruton's tyrosine kinase
- PI3K phosphoinositide-3-kinase
- the combination therapy is of use for treating hematopoietic cancers, such as ALL or CLL.
- the human CLL cell line, JVM-3 was grown s.c. in SCID mice. Once tumors reached ⁇ 0.2 cm 3 , they were divided into treatment groups of either IMMU-114 or rituximab (200, 100, or 50 mg, twice weekly for 4 weeks). Study survival endpoint was tumor progression to >1.0 cm 3 .
- JMV-3 was treated with various concentrations of either a Btk inhibitor (ibrutinib) or PI3K inhibitor (idelalisib) in the presence of a constant amount of IMMU-114. IC 50 -values were determined, data were normalized, and isobolograms generated for each inhibitor to determine overall effect.
- ALL MN-60 cells were injected i.v. into SCID mice.
- mice received IMMU-114 (50 or 25 mg, 2 ⁇ weekly for 4 weeks) or doxorubicin (3 ⁇ 20 mg qdx3d induction phase, followed by a 60-mg bolus injection maintenance phase on week 3).
- Disease progression was declared upon the onset of hind-limb paralysis.
- mice with JVM-3 (CLL) tumors had a median survival time (MST) of 14 days for saline controls, while therapy with rituximab significantly improved survival (P ⁇ 0.0102); the MST was only 19 days for the two highest doses.
- mice treated with IMMU-114 had a MST >42 days for all three doses tested (P ⁇ 0.0001), providing an overall superior tumor growth control over rituximab (P ⁇ 0.0116).
- an additive effect was observed in JVM-3 when IMMU-114 was combined with either ibrutinib or idelalisib.
- MST doxorubicin-treated mice
- IMMU-114 at both the 50 and 25 mg doses, provided a significant survival benefit compared to both saline control and doxorubicin-treated animals (MST>39 days, P ⁇ 0.0001).
- IMMU-114 therapy was well tolerated in all these studies, as evidenced by no significant loss in weight.
- FIG. 1 shows the relative efficacies of IMMU-114 (anti-HLA-DR) vs. rituximab (anti-CD20) in CLL xenografts.
- C.B.-17 SCID mice were injected s.c.
- IMMU-114 had significant anti-tumor effects compared to saline or rituximab at every dose tested (P ⁇ 0.0116; AUC) ( FIG. 1 ).
- the survival data for CLL-bearing nude mice treated with IMMU-114 or rituximab at 14 to 18 days of treatment is summarized in Table 2, showing an area under the curve survival comparison for the two groups.
- IMMU-114 was significantly more efficacious than rituximab.
- the P-value (AUC) was 0.0004.
- mice treated with IMMU-114 still showed significantly improved survival at all dosages when compared to rituximab-treated mice.
- the median survival was 46 days for IMMU-114 treated mice, compared to 18 days for rituximab-treated mice (P-value ⁇ 0.0001).
- Combination therapy with the IMMU-114 antibody and the exemplary Bruton's tyrosine kinase inhibitor ibrutinib was observed in CLL (JVM-3) xenografts.
- Dose/response curves for each agent alone were first tested to determine single agent IC 10 , IC 20 , or IC 30 -values after a 96-h incubation ( FIG. 3 , FIG. 4 ).
- IMMU-114 was tested in JVM-3 across a range of concentrations (i.e., dose/response curves) ( FIG. 3 ).
- One set of wells only received IMMU-114, while another set received IMMU-114 as dose/response with a constant amount of ibrutinib (e.g., IC 10 -concentration) ( FIG. 3 ).
- ibrutinib e.g., IC 10 -concentration
- Two other sets used ibrutinib at IC 20 or IC 30 concentrations ( FIG. 3 ).
- the IC 50 -value was determined from these data. As shown in FIG.
- the IC 50 values for IMMU-114 ranged from 1.89 ⁇ 10 ⁇ 9 M in the absence of ibrutinib to 1.66 ⁇ 10 ⁇ 9 M in 0.25 ⁇ M ibrutinib, 0.66 ⁇ 10 ⁇ 9 M in 0.5 ⁇ M ibrutinib, and 0.20 ⁇ 10 ⁇ 9 M in 1 ⁇ M ibrutinib.
- IMMU-114 i.e., IC 10 -, IC20-, or IC 30 -concentrations
- the IC 50 value for ibrutinib varied from 2.37 ⁇ 10 ⁇ 6M in the absence of IMMU-114, to 0.94 ⁇ 10 ⁇ 6 M in 0.25 nM IMMU-114, 0.48 ⁇ 10 ⁇ 6 M in 0.50 nM IMMU-114 and 0.37 ⁇ 10 ⁇ 6 M in 0.65 nM IMMU-114.
- hL243 designates the same antibody as IMMU-114.
- One set of wells only received idelalisib, while another set received idelalisib as dose/response with a constant amount of IMMU-114 (e.g., ⁇ IC 10 -concentration) ( FIG. 6 ).
- Two other sets use IMMU-114 at IC 20 or IC 30 concentrations ( FIG. 6 ).
- the IC 50 value was determined from these graphed data, at each concentration of IMMU-114.
- IC 50 for idelalisib determined ranged from 14.26 ⁇ M in the absence of IMMU-114 to 8.28 ⁇ M in 0.25 nM IMMU-114, 6.0 ⁇ M in 0.5 nM IMMU-114 to 4.45 ⁇ M in 0.65 nM IMMU-114.
- mice treated with doxorubicin alone did not respond to treatment and were no different from saline control ( FIG. 8 ).
- both doses of IMMU-114 of 25 or 50 ⁇ g provided ⁇ 2-fold improvement in survival compared to all control groups.
- there was a dose/response observed in that mice treated with 50 mg IMMU-114 had a significant survival benefit in comparison to mice treated with 25 mg (P 0.0336).
- IMMU-114 In vitro, the combination of IMMU-114 and two different kinase inhibitors was evaluated in CLL.
- IMMU-114 and the Bruton's kinase inhibitor, ibrutinib combined to provide a synergistic growth inhibitory interaction, whereas the combination with a PI3K inhibitor, idelalisib, resulted in an additive effect.
- the antibody was given in combination with the Bruton's kinase inhibitor ibrutinib, administered orally at a dosage of 420 mg daily. After 6 weeks, evaluation of the patient's hematological and lab values indicate that she has shown a partial response to the combination therapy.
- follicular NHL Seventeen patients with follicular NHL who have not shown a response to rituximab and an alkylating agent, or relapsed within 6 months after receipt of those therapies receive 200 mg IMMU-114, injected s.c. twice weekly, in combination with the PI3K inhibitor idelalisib, administered orally at 150 mg twice daily, until the disease progresses or the patient withdraws from the study. Responses are assessed by CT scans, with other evaluations including adverse events, B-cell blood levels, serum IMMU-114 levels and human anti-IMMU-114 (HAHA) titers.
- HAHA human anti-IMMU-114
- Electrospray mass spectrum showed peaks at m/e 1753.3 (M+H), m/e 1751.6 (M ⁇ H), 1864.5 (M+TFA), consistent with structure.
- deprotection of the penultimate intermediate (0.22 g) with a mixture of dichloroacetic acid (0.3 mL) and anisole (0.03 mL) in methylene chloride (3 mL), followed by precipitation with ether yielded 0.18 g (97% yield) of CL2A-SN-38; (7) in Scheme-3) as light yellow powder.
- Electrospray mass spectrum showed peaks at m/e 1480.7 (M+H), 1478.5 (M ⁇ H), consistent with structure.
- the anti-CEACAM-5 humanized MAb, hMN-14 also known as labetuzumab
- the anti-CD22 humanized MAb, hLL2 also known as epratuzumab
- the anti-CD20 humanized MAb, hA20 also known as veltuzumab
- the anti-EGP-1 humanized MAb, hRS7, and anti-mucin humanized MAb, hPAM4 also known as clivatuzumab
- Each antibody was reduced with dithiothreitol (DTT), used in a 50-to-70-fold molar excess, in 40 mM PBS, pH 7.4, containing 5.4 mM EDTA, at 37° C. (bath) for 45 min.
- DTT dithiothreitol
- the reduced product was purified by size-exclusion chromatography and/or diafiltration, and was buffer-exchanged into a suitable buffer at pH 6.5.
- the thiol content was determined by Ellman's assay, and was in the 6.5-to-8.5 SH/IgG range.
- the antibodies were reduced with Tris (2-carboxyethyl) phosphine (TCEP) in phosphate buffer at pH in the range of 5-7, followed by in situ conjugation.
- TCEP Tris (2-carboxyethyl) phosphine
- the reduced MAb was reacted with ⁇ 10-to-15-fold molar excess of CL2A-SN-38 using DMSO at 7-15% v/v as co-solvent, and incubating for 20 min at ambient temperature.
- the conjugate was purified by centrifuged SEC, passage through a hydrophobic column, and finally by ultrafiltration-diafiltration.
- the product was assayed for SN-38 by absorbance at 366 nm and correlating with standard values, while the protein concentration was deduced from absorbance at 280 nm, corrected for spillover of SN-38 absorbance at this wavelength. This way, the SN-38/MAb substitution ratios were determined.
- the purified conjugates were stored as lyophilized formulations in glass vials, capped under vacuum and stored in a ⁇ 20° C. freezer.
- MSR molar substitution ratios
- IMMU-140 Treatment of Relapsed Chronic Lymphocytic Leukemia with IMMU-140 (IMMU-140) and Idelalisib
- the IMMU-140 is administered i.v. at 6 mg/kg on days 1 and 8 and idelalisib is administered at a dosage of 100 mg p.o. on days 1, 7 and 14 of the cycle, then the cycle is repeated. After 4 cycles, evaluation shows that the patient's hematological parameters improve and his circulating CLL cells appear to be decreasing in number. The therapy is resumed for another 3 cycles, after which his hematological and lab values indicate that he has a partial response.
- a 60-year-old male presents with abdominal pain and the presence of a palpable mass.
- the patient has CT and FDG-PET studies confirming the presence of the mass with pathologic adenopathies in the mediastinum, axillary, and neck nodes. Lab tests are unremarkable except for elevated LDH and beta-2-microglobulin.
- Bone marrow biopsy discloses several paratrabecular and perivascular lymphoid aggregates. The final diagnosis is grade-2 follicular lymphoma, stage IVA, with a FLIPI score of 4. The longest diameter of the largest involved node is 7 cm.
- the patient is given combination therapy with a humanized anti-HLA-DR-SN-38 conjugate (IMMU-140), plus rucaparib and paclitaxel, on a 21-day cycle.
- IMMU-140 humanized anti-HLA-DR-SN-38 conjugate
- the ADC is given at 6 mg/kg on days 7 and 14
- rucaparib is administered at 10 mg/m 2 on days 1, 8 and 15
- paclitaxel is administered at 125 mg/m 2 on days 1, 7 and 14 of the cycle.
- bone marrow and imaging (CT) evaluations show a partial response, where the measurable lesions decrease by about 60% and the bone marrow is much less infiltrated.
- LDH and beta-2-microglobulin titers also decrease.
- the patient is a 62 year-old male with relapsed diffuse large B-cell lymphoma (DLBCL).
- DLBCL diffuse large B-cell lymphoma
- IMMU-114 plus paclitaxel on a 21-day cycle.
- the anti-HLA-DR mAb is administered at a dose of 12 mg/kg on days 1 and 7 and paclitaxel is administered at 175 mg/m 2 on days 1, 7 and 14 of the cycle.
- the patient is evaluated by CT imaging, and his total tumor bulk is measured and shows a decrease of 35% (partial response), which appears to be maintained over the next 3 months.
- Side effects are only thrombocytopenia and grade 1 nausea and vomiting after therapy, which resolve within 2 weeks. No pretherapy for reducing infusion reactions is given.
- the patient is a 41-year-old woman presenting with low-grade follicular lymphoma, with measurable bilateral cervical and axillary lymph nodes (2-3 cm each), mediastinal mass of 4 cm diameter, and an enlarged spleen.
- She is given IMMU-140 in combination with rucaparib, with ADC administered at 10 mg/kg on day 1 and rucaparib at 12 mg/m 2 on days 1, 8 and 15.
- her tumor measurements by CT show a reduction of 80%.
- She is then given 2 additional courses of therapy, and CT measurements indicate that a complete response is achieved. This is confirmed by FDG-PET imaging.
- P2PDox Pro-2-pyrrolinodoxorubicin
- Conjugates were also prepared for hPAM4-P2PDox, hLL2-P2PDox and RFB4-P2PDox, with similar protein recovery and purity (not shown).
- Serum stability of prototypical P2PDox conjugate was determined by incubating in human serum at a concentration of 0.2 mg/mL at 37° C. The incubate was analyzed by HPLC using butyl hydrophobic interaction chromatography (HIC) column in which there was good retention time separation between the peak due to free drug and that due to conjugate or higher molecular weight species. This analysis showed that there was no release of free drug from the conjugate, suggesting high serum stability of the conjugate.
- HIC butyl hydrophobic interaction chromatography
- the P2PDox conjugate was held tightly to the antibody because it cross-linked the peptide chains of the antibody together.
- the cross-linking stabilizes the attachment of the drug to the antibody so that the drug is only released intracellularly after the antibody is metabolized.
- the cross-linking assists in minimizing toxicity, for example cardiotoxicity, that would result from release of free drug in circulation.
- Previous use of 2-PDox peptide conjugates failed because the drug cross-linked the peptide to other proteins or peptides in vivo. With the present conjugates, the P2PDox is attached to interchain disulfide thiol groups while in the prodrug form.
- the prodrug protection is rapidly removed in vivo soon after injection and the resulting 2-PDox portion of the conjugate cross-links the peptide chains of the antibody, forming intramolecular cross-linking within the antibody molecule. This both stabilizes the ADC and prevents cross-linking to other molecules in circulation.
- Tumor size was determined by caliper measurements of length (L) and width (W) with tumor volume calculated as (L ⁇ W 2 )/2. Tumors were measured and mice weighed twice a week. Mice were euthanized if their tumors reached >1 cm 3 in size, lost greater than 15% of their starting body weight, or otherwise became moribund.
- Statistical analysis for the tumor growth data was based on area under the curve (AUC) and survival time. Profiles of individual tumor growth were obtained through linear curve modeling. An f-test was employed to determine equality of variance between groups prior to statistical analysis of growth curves. A two-tailed t-test was used to assess statistical significance between all the various treatment groups and non-specific controls.
- ADCs Antibody-drug conjugates carrying as much as 8 ultratoxic drugs/MAb are known to clear faster than unmodified MAb and to increase off-target toxicity, a finding that has led to the current trends to use drug substitutions of ⁇ 4 (Hamblett et al., 2004, Clin Cancer Res 10:7063-70). Conjugates were prepared and evaluated with mean drug/MAb substitution ratios (MSRs) of ⁇ 6:1 and ⁇ 3:1.
- MSRs mean drug/MAb substitution ratios
- Anti-TROP-2 antibody conjugate hRS7-P2PDox
- hRS7-P2PDox was evaluated in nude mice bearing NCI-N87 human gastric cancer xenografts by administering a single bolus protein dose of 9 mg/kg, 6.75 mg/kg, 4.5 mg/kg, 2.25 mg/kg, or 1 mg/kg.
- the therapy was started when the mean tumor volume (mTV) was 0.256 cm 3 .
- mTV in the saline control group was 0.801 ⁇ 0.181 cm 3 which was significantly larger than that in mice treated with 9, 6.75, 4.5, or 2.25 mg/kg dose with mTV of 0.211 ⁇ 0.042 cm 3 , 0.239 ⁇ 0.0.054 cm 3 , 0.264 ⁇ 0.087 cm 3 , and 0.567 ⁇ 0.179 cm 3 , respectively (P ⁇ 0.0047, one tailed t-test). From these, the minimum effective dose was judged to be 2.25 mg/kg, while 9 mg/kg represented MTD.
- mice An MTD study comparing 2-PDox and P2PDox conjugates of prototype antibody, hLL1, in mice demonstrated that the P2PDox conjugate was much more potent (not shown).
- the MTD of a single i.v. injection was between 100 and 300 ⁇ g.
- the MTD of multiple injections, at a schedule of every four days for a total of four injections (q4dx4) was then determined, using protein doses between 25 ⁇ g to 150 ⁇ g per injection. At these doses, a cumulative dose of between 100 and 600 ⁇ g was given to the animals. Table 6 below summarizes the various groups.
- mice treated with 25 ⁇ g P2PDox-ADC continue to show no signs of toxicity (not shown). This is a cumulative dose of 100 ⁇ g which was also the dose tolerated when administered as a single injection (not shown). Therefore, the MTD for multiple injections of a P2PDox-ADC in mice is 25 ⁇ g q4dx4 from this experiment.
- a more detailed analysis of data and repetition of the experiment established the MTD for fractionated dosing to be 45 ⁇ g of protein dose of the conjugate, administered every 4 days for 2 weeks (45 q4dx4 schedule).
- hRS7-P2PDox and hMN-15-P2PDox were cytotoxic to MDA-MB-468, AG S, NCI-N87 and Capan-1 solid tumor cell lines (not shown).
- hMN-14-P2PDox was cytotoxic to Capan-1, BxPC-3 and AsPC-1 human pancreatic tumor lines and AGS, NCI-N87 and LS147T human gastric and colonic tumor lines (not shown).
- hLL2-P2PDOx was cytotoxic to Daudi, Raji, Ramos and JVM-3 hematopoietic tumor lines (not shown).
- IC 50 values for the conjugates were in the nanomolar concentration range (not shown).
- mice receiving 90 ⁇ g weekly ⁇ 2 of hRS7-P2PDox 9 of 9 mice were alive at day 94 (not shown).
- mice receiving a single dose of 180 ⁇ g of hRS7-P2PDox 8 of 9 mice were alive at day 94 (not shown).
- the control hA20 conjugate had no effect on survival (not shown).
- a toxicity study showed that the three dosage schedules of hRS7-P2PDox resulted in similarly low levels of toxicity (not shown).
- the hRS7-P2PDox conjugate was also effective in Capan-1 pancreatic cancer (not shown) and was more effective at inhibiting tumor growth than a hRS7-SN-38 conjugate (not shown).
- the hPAM4-P2PDox conjugate was also more effective at inhibiting growth of Capan-1 human pancreatic cancer than an hPAM4-SN-38 conjugate (not shown).
- mice were alive in the saline control, 10 of 10 mice were alive in mice treated twice weekly ⁇ 2 weeks with 45 ⁇ g of hPAM4-P2PDox, 2 of 10 mice were alive in mice treated twice weekly ⁇ 2 weeks with 45 ⁇ g of hA20-P2PDox, 0 of 10 mice were alive in mice treated twice weekly ⁇ 4 weeks with 250 ⁇ g of hPAM4-SN-38, and 0 of 10 mice were alive in mice treated twice weekly ⁇ 4 weeks with 250 ⁇ g of h20-SN-38.
- hRS7-P2PDox was substantially more effective than hRS7-SN-38 at inhibiting growth of PxPC-3 pancreatic cancer (not shown) and was slightly more effective than hRS7-SN-38 at inhibiting growth of MDA-MB-468 breast cancer (not shown).
- hRS7-ADC conjugates were determined in comparison to hRS7 IgG (not shown).
- PBMCs were purified from blood purchased from the Blood Center of New Jersey.
- a Trop-2-positive human pancreatic adenocarcinoma cell line (BxPC-3) was used as the target cell line with an effector to target ratio of 100:1.
- ADCC mediated by hRS7 IgG was compared to hRS7-Pro-2-PDox, hRS7-CL2A-SN-38, and the reduced and capped hRS7-NEM. All were used at 33.3 nM. Overall activity was low, but significant (not shown).
- the ADC conjugates are were purified and buffer-exchanged with 2-(N-morpholino)ethanesulfonic acid (MES), pH 6.5, and further formulated with trehalose (25 mM final concentration) and polysorbate 80 (0.01% v/v final concentration), with the final buffer concentration becoming 22.25 mM as a result of excipient addition.
- the formulated conjugates are lyophilized and stored in sealed vials, with storage at 2° C.-8° C.
- the lyophilized ADCs are stable under the storage conditions and maintain their physiological activities.
- IMMU-114 (hL243) is a humanized anti-HLA-DR IgG4 monoclonal antibody engineered to lack effector-cell functions, but retains HLA-DR binding and a broad range of antitumor effects in diverse hematological neoplasms (Stein et al., Blood. 2010; 115:5180-90).
- NHL non-Hodgkin's lymphoma
- CLL chronic lymphatic leukemia
- AML has proven to be resistant to the antitumor effects of IMMU-114, despite high expression levels of HLA-DR.
- IMMU-114 has demonstrated a range of antitumor effects from a low of 9% to a high of 69%.
- ADC antibody-drug conjugate
- mice treated with IMMU-140 succumbed to disease progression quickly, with a median survival time (MST) of only 14 and 15 days, respectively.
- MST median survival time
- IMMU-140 anti-HLA-DR ADC proved to be superior to IMMU-114 (which is active clinically in NHL and CLL) in both AML and ALL xenografts and beneficial in MM.
- IMMU-114-refractive AML IMMU-140 demonstrated a significant antitumor effect without any undue toxicity. The data show that this new ADC is of use in these intractable malignancies.
- mice were monitored daily and were sacrificed at disease progression, characterized by the onset of hind-limb paralysis or loss of more than 15% body weight. Survival was analyzed using Kaplan-Meier plots (log-rank analysis), using the Prism GraphPad Software (v6.05) package (Advanced Graphics Software, Inc.; Encinitas, Calif.).
- mice treated with IMMU-140 succumbed to disease progression quickly, with a median survival time (MST) of only 14 and 15 days, respectively ( FIG. 9 ).
- Therapy with IMMU-140 was well tolerated, as evidenced by no significant loss in body weight (not shown).
- mice were injected with the MN-60 human ALL cell line (1 ⁇ 10 7 cells).
- the mice were randomized into five treatment groups of 10 mice each. Five days later mice began therapy.
- IMMU-114 was administered as 500 ⁇ g s.c. injections twice weekly for four weeks.
- Treatment groups are summarized in Table 8 below.
- mice were monitored daily and were sacrificed at disease progression, characterized by the onset of hind-limb paralysis or loss of more than 15% body weight. Survival was analyzed using Kaplan-Meier plots (log-rank analysis), using the Prism GraphPad Software (v6.05) package (Advanced Graphics Software, Inc.; Encinitas, Calif.).
- IMMU-114 P ⁇ 0.0001
- three mice in the IMMU-140 group (30%) were still alive. Upon necropsy, there was no visible evidence of disease in these mice (i.e., no internal tumors found). Therapy with IMMU-140 was well tolerated, as evidenced by no significant loss in body weight.
- mice were irradiated with 2 Gy one day before being injected i.v. with CAG cells (1 ⁇ 10 7 cells). At the time of cell injection, the mice were randomized into eight treatment groups of 10 mice each. Five days later mice began therapy as outlined in the table below.
- bortezomib is administered to MM patients at 1.3 mg/m 2 twice a week for two weeks followed by one week rest before repeating. A clinical dose of 1.3 mg/m 2 is equivalent to 0.43 mg/kg to mice. For this study, mice were administered bortezomib (15 ⁇ g; 0.89 mg/kg) weekly for four weeks only. Treatment groups are summarized Table 9.
- mice were monitored daily and were sacrificed at disease progression, characterized by the onset of hind-limb paralysis or loss of more than 15% body weight. Survival was analyzed using Kaplan-Meier plots (log-rank analysis), using the Prism GraphPad Software (v6.05) package (Advanced Graphics Software, Inc.; Encinitas, Calif.).
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Abstract
Description
Rituximab heavy chain variable region sequence |
(SEQ ID NO: 7) |
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV |
HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKAEP |
KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS |
HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK |
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTC |
LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW |
QQGNVFSCSVMHEALHNHYTQKSLSLSPGK |
Veltuzumab heavy chain variable region |
(SEQ ID NO: 8) |
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV |
HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP |
KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS |
HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK |
EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC |
LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW |
QQGNVFSCSVMHEALHNHYTQKSLSLSPGK |
TABLE 1 |
Allotypes of Rituximab vs. Veltuzumab |
Heavy chain position and | ||
associated allotypes |
Complete | 214 | 356/358 | 431 | |
allotype | (allotype) | (allotype) | (allotype) | |
Rituximab | G1m17, 1 | K | 17 | D/L | 1 | A | — |
Veltuzumab | G1m3 | R | 3 | E/M | — | A | — |
TABLE 2 |
Area under the curve comparison between |
IMMU-114 and rituximab for CLL. |
Area under the curve comparisons between IMMU-114 and |
Rituximab treated JVM-3 tumor-bearing mice. |
Time of | Tumor Volumes (cm3) | P-Value | |
Treatments | Comparison | On that day (mean ± s.d.) | (AUC) |
IMMU-114 | Rituximab | Up to therapy | 0.347 ± 0.120 vs. | 0.0004 |
(200 μg) | (200 μg) | |
1.017 ± 0.266 | |
IMMU-114 | Rituximab | Up to therapy | 0.242 ± 0.101 vs. | 0.0116 |
(100 μg) | (100 μg) | |
0.643 ± 0.286 | |
IMMU-114 | Rituximab | Up to therapy | 0.270 ± 0.094 vs. | 0.0039 |
(50 μg) | (50 μg) | |
0.765 ± 0.307 | |
TABLE 3 |
Survival cares comparing efficacy of IMMU-114 |
(anti-HLA-DR) vs. rituximab (anti-CD20) |
Survival curve comparisons between IMMU-114 and Rituximab |
treated JVM-3 tumor-bearing mice. |
Median Survival | P-Value | |
Treatments | Times | (log-rank) |
IMMU-114 | Rituximab (200 μg) | 46 days versus 18 days | <0.0001 |
(200 μg) | |||
IMMU-114 | Rituximab (100 μg) | 54 days versus 18 days | 0.0107 |
(100 μg) | |||
IMMU-114 | Rituximab (50 μg) | 42 days versus 19 days | <0.0001 |
(50 μg) | |||
TABLE 4 |
SN-38/MAb Molar substitution ratios (MSR) in some conjugates |
MAb | Conjugate | MSR |
hMN-14 | hMN-14-CL2A-SN-38 | 6.1 |
hRS7 | hRS7-CL2A-SN-38 | 5.8 |
hA20 | hA20-CL2A-SN-38 | 5.8 |
hLL2 | hLL2-CL2A-SN-38 | 5.7 |
hPAM4 | hPAM4-CL2A-SN-38 | 5.9 |
TABLE 5 |
Exemplary P2PDox-Antibody Conjugates |
% | HPLC |
Protein | P2PDo | Free | ||||
Conjugate | Lot | recover | x/IgG | Aggr. | |
|
1 | hIMMU-31- | II22-138 | 75.0% | 7.39 | 1.9% | 0.26% |
P2PDox | ||||||
2 | hA20-P2PDox | II22-135 | 85.7% | 6.79 | <2% | <0.1% |
3 | hLL1-P2PDox | II22-145 | 88.6% | 7.10 | 2.8% | 0.2% |
4 | hRS7-P2PDox | II22-142 | 80.1% | 7.17 | 1.8% | 0.12% |
5 | hMN15- | II22-180 | 74.9% | 6.87 | 1.1% | 0.46 |
P2PDox | ||||||
6 | hMN-14- | II22-183 | 80.2% | 6.78 | 2.1% | 0.53% |
P2PDox | ||||||
TABLE 6 |
Dosage and Schedule for MTD of antibody- |
12 Female Athymic Nude Mice |
Group | N | Treatment | |
||
1 | 3 | 25 μg i.v. |
100 μg | ||
2 | 3 | 50 μg i.v. q4dx4 | 200 μg | ||
3 | 3 | 100 μg i.v. q4dx4 | 400 |
||
4 | 3 | 150 μg i.v. q4dx4 | 600 μg | ||
TABLE 7 |
IMMU-114 versus IMMU-140 Efficacy in a Human |
AML Disease Model (MOLM-14). |
Schedule | |||||
( |
|||||
Group | (N) | Treatment | injection) | ||
1 | 5 | Saline | Twice weekly × 4 wks | ||
(100 μL i.p.) | |||||
2 | 5 | IMMU-140 | Twice weekly × 4 wks | ||
(500 μg i.p.) | |||||
3 | 5 | IMMU-140 | Twice weekly × 4 wks | ||
(250 μg i.p.) | |||||
4 | 5 | hMN14-SN-38 | Twice weekly × 4 wks | ||
(500 μg i.p.) | |||||
5 | 5 | hMN14-SN-38 | Twice weekly × 4 wks | ||
(250 μg i.p.) | |||||
6 | 5 | IMMU-114 | Twice weekly × 4 wks | ||
(500 μg s.c.) | |||||
TABLE 8 |
Treatment of ALL with IMMU-140 vs. IMMU-114 |
IMMU-114 and IMMU-140 Efficacy in a Human |
ALL Disease Model (MN-60). |
Schedule | |||||
( |
|||||
Group | N | Treatment | injection) | ||
1 | 10 | Saline | Twice weekly × 4 wks | ||
(100 μL i.p.) | |||||
2 | 10 | IMMU-114 | Twice weekly × 4 wks | ||
(500 μg s.c.) | |||||
3 | 10 | IMMU-140 | Twice weekly × 4 wks | ||
(500 μg i.p.) | |||||
4 | 10 | hMN-14 | Twice weekly × 4 wks | ||
(500 μg s.c.) | |||||
5 | 10 | hMN14-SN-38 | Twice weekly × 4 wks | ||
(500 μg i.p.) | |||||
TABLE 9 |
Efficacy of IMMU-114 vs. IMMU-140 in multiple myeloma xenografts |
IMMU-114 and IMMU-140 Efficacy in a Human MM Disease Model |
(CAG). |
Schedule | |||
( |
|||
Group | N | Treatment | injection) |
1 | 10 | Saline | Twice weekly × 4 wks |
(100 μL i.p.) | |||
2 | 10 | IMMU-114 | Twice weekly × 4 wks |
(500 μg i.p.) | |||
3 | 10 | IMMU-140 | Twice weekly × 4 wks |
(500 μg i.p.) | |||
4 | 10 | Bortezomib | Weekly × wks |
(15 μg; ~1 mg/kg i.v.) | |||
5 | 10 | IMMU-114 | Twice weekly × 4 wks |
(500 μg i.p.) | + | ||
+ | Weekly × 4 wks | ||
Bortezomib | |||
(15 μg; ~1 mg/kg i.v.) | |||
6 | 10 | IMMU-140 | Twice weekly × 4 wks |
(500 μg i.p.) | + | ||
+ | Weekly × 4 wks | ||
Bortezomib | |||
(15 μg; ~1 mg/kg i.v.) | |||
7 | 10 | hMN-14 IgG | Twice weekly × 4 wks |
(500 μg i.p.) | + | ||
+ | Weekly × 4 wks | ||
Bortezomib | |||
(15 μg; ~1 mg/kg i.v.) | |||
8 | 10 | hMN14-SN-38 | Twice weekly × 4 wks |
(500 μg i.p.) | + | ||
+ | Weekly × 4 wks | ||
Bortezomib | |||
(15 μg; ~1 mg/kg i.v.) | |||
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Citations (145)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4036945A (en) | 1976-05-03 | 1977-07-19 | The Massachusetts General Hospital | Composition and method for determining the size and location of myocardial infarcts |
US4046722A (en) | 1975-02-04 | 1977-09-06 | G. D. Searle & Co. Limited | Immunological materials |
US4200690A (en) | 1976-12-16 | 1980-04-29 | Millipore Corporation | Immunoassay with membrane immobilized antibody |
US4331647A (en) | 1980-03-03 | 1982-05-25 | Goldenberg Milton David | Tumor localization and therapy with labeled antibody fragments specific to tumor-associated markers |
US4359457A (en) | 1980-09-30 | 1982-11-16 | Neville Jr David M | Anti Thy 1.2 monoclonal antibody-ricin hybrid utilized as a tumor suppressant |
US4699784A (en) | 1986-02-25 | 1987-10-13 | Center For Molecular Medicine & Immunology | Tumoricidal methotrexate-antibody conjugate |
US4704692A (en) | 1986-09-02 | 1987-11-03 | Ladner Robert C | Computer based system and method for determining and displaying possible chemical structures for converting double- or multiple-chain polypeptides to single-chain polypeptides |
EP0253202A2 (en) | 1986-06-30 | 1988-01-20 | Oncogen | Novel immunoconjugates and methods for their use in tumor therapy |
EP0306943A2 (en) | 1987-09-10 | 1989-03-15 | Neorx Corporation | Immunconjugates joined by thioether bonds having reduced toxicity and improved selectivity |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US4824659A (en) | 1985-06-07 | 1989-04-25 | Immunomedics, Inc. | Antibody conjugates |
EP0332865A2 (en) | 1988-03-17 | 1989-09-20 | American Cyanamid Company | Suppression of B-cells in mammals |
US4916213A (en) | 1983-02-22 | 1990-04-10 | Xoma Corporation | Ribosomal inhibiting protein-immunoglobulin conjugates with specificity for tumor cell surface antigens, and mixtures thereof |
US4918163A (en) | 1985-09-27 | 1990-04-17 | Pfizer Inc. | Monoclonal antibodies specific for lipid-A determinants of gram negative bacteria |
US4925922A (en) | 1983-02-22 | 1990-05-15 | Xoma Corporation | Potentiation of cytotoxic conjugates |
US4932412A (en) | 1986-12-18 | 1990-06-12 | Immunomedics, Inc. | Intraoperative and endoscopic tumor detection and therapy |
US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
WO1990009196A1 (en) | 1989-02-10 | 1990-08-23 | Celltech Limited | Cross-linked antibodies and processes for their preparation |
WO1991011465A1 (en) | 1990-01-26 | 1991-08-08 | Immunomedics, Inc. | Vaccines against cancer and infectious diseases |
WO1991013974A1 (en) | 1990-03-14 | 1991-09-19 | The Biomembrane Institute | Monoclonal antibody and immunoconjugates for the treatment and detection of b cell disorders |
US5057313A (en) | 1986-02-25 | 1991-10-15 | The Center For Molecular Medicine And Immunology | Diagnostic and therapeutic antibody conjugates |
US5106955A (en) | 1987-03-26 | 1992-04-21 | Teijin Limited | Process for preparation of antibody conjugates |
US5112954A (en) | 1988-02-26 | 1992-05-12 | Neorx Corporation | Method of enhancing the effect of cytotoxic agents |
US5122368A (en) | 1988-02-11 | 1992-06-16 | Bristol-Myers Squibb Company | Anthracycline conjugates having a novel linker and methods for their production |
US5134075A (en) | 1989-02-17 | 1992-07-28 | Oncogen Limited Partnership | Monoclonal antibody to novel antigen associated with human tumors |
EP0510949A2 (en) | 1991-04-23 | 1992-10-28 | Sangstat Medical Corporation | Cytomodulating conjugates of members of specific binding pairs |
US5171665A (en) | 1989-04-17 | 1992-12-15 | Oncogen | Monoclonal antibody to novel antigen associated with human tumors |
US5196337A (en) | 1989-04-24 | 1993-03-23 | Sumitomo Chemical Company, Limited | Human monoclonal antibody, and its production and use |
US5204095A (en) | 1980-04-09 | 1993-04-20 | National Research Development Corporation | Monoclonal antibodies against hepatitis B virus |
US5229275A (en) | 1990-04-26 | 1993-07-20 | Akzo N.V. | In-vitro method for producing antigen-specific human monoclonal antibodies |
WO1994027638A1 (en) | 1993-05-21 | 1994-12-08 | Dana-Farber Cancer Institute, Inc. | Monoclonal antibodies that block ligand binding to the cd22 receptor in mature b cells |
WO1994029451A2 (en) | 1993-06-16 | 1994-12-22 | Celltech Limited | Humanised antibodies |
WO1995009917A1 (en) | 1993-10-07 | 1995-04-13 | The Regents Of The University Of California | Genetically engineered bispecific tetravalent antibodies |
US5443953A (en) | 1993-12-08 | 1995-08-22 | Immunomedics, Inc. | Preparation and use of immunoconjugates |
WO1996004925A1 (en) | 1994-08-12 | 1996-02-22 | Immunomedics, Inc. | Immunoconjugates and humanized antibodies specific for b-cell lymphoma and leukemia cells |
US5525338A (en) | 1992-08-21 | 1996-06-11 | Immunomedics, Inc. | Detection and therapy of lesions with biotin/avidin conjugates |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5565215A (en) | 1993-07-23 | 1996-10-15 | Massachusettes Institute Of Technology | Biodegradable injectable particles for imaging |
US5567610A (en) | 1986-09-04 | 1996-10-22 | Bioinvent International Ab | Method of producing human monoclonal antibodies and kit therefor |
US5593676A (en) | 1993-08-02 | 1997-01-14 | The Leland Stanford Junior University | Method of killing B cells using antibodies which bind CDIM |
US5618920A (en) | 1985-11-01 | 1997-04-08 | Xoma Corporation | Modular assembly of antibody genes, antibodies prepared thereby and use |
US5620708A (en) | 1993-02-22 | 1997-04-15 | Alza Corporation | Compositions and methods for the oral delivery of active agents |
US5633425A (en) | 1990-08-29 | 1997-05-27 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5679640A (en) | 1991-02-12 | 1997-10-21 | Cytel Corporation | Immunosuppressant peptides |
US5686072A (en) | 1992-06-17 | 1997-11-11 | Board Of Regents, The University Of Texas | Epitope-specific monoclonal antibodies and immunotoxins and uses thereof |
US5698178A (en) | 1994-08-05 | 1997-12-16 | Immunomedics, Inc. | Polyspecific immunoconjugates and antibody composites for targeting the multidrug resistant phenotype |
US5708146A (en) | 1992-01-23 | 1998-01-13 | Bristol-Myers Squibb Company | Thioether conjugates |
WO1998004281A1 (en) | 1996-07-26 | 1998-02-05 | Smithkline Beecham Corpration | Improved method of treating immune cell mediated systemic diseases |
US5716595A (en) | 1992-05-06 | 1998-02-10 | Immunomedics, Inc. | Intraperative, intravascular and endoscopic tumor and lesion detection and therapy with monovalent antibody fragments |
US5736119A (en) | 1993-05-17 | 1998-04-07 | Immunomedics, Inc. | Detection and therapy of lesions with biotin/avidin-metal chelating protein conjugates |
US5750105A (en) | 1991-07-25 | 1998-05-12 | Idec Pharmaceuticals Corporation | Recombinant antibodies for human therapy |
US5776456A (en) | 1992-11-13 | 1998-07-07 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US5792845A (en) | 1994-04-26 | 1998-08-11 | The Children's Medical Center Corporation | Nucleotides encoding angiostatin protein and method of use |
US5792852A (en) | 1992-11-16 | 1998-08-11 | Cancer Research Fund Of Contra Costa | Polynucleotides encoding modified antibodies with human milk fat globule specificity |
US5795967A (en) | 1984-07-05 | 1998-08-18 | Genentech, Inc. | Tumor necrosis factor antagonists and their use |
US5798554A (en) | 1995-02-24 | 1998-08-25 | Consorzio Per La Ricerca Sulla Microelettronica Nel Mezzogiorno | MOS-technology power device integrated structure and manufacturing process thereof |
WO1998042378A1 (en) | 1997-03-24 | 1998-10-01 | Immunomedics, Inc. | Immunotherapy of b-cell malignancies using anti-cd22 antibodies |
US5817307A (en) | 1986-11-06 | 1998-10-06 | The Texas A&M University System | Treatment of bacterial infection with oral interferon-α |
US5824701A (en) | 1993-10-20 | 1998-10-20 | Enzon, Inc. | Taxane-based prodrugs |
WO1998050435A1 (en) | 1997-05-02 | 1998-11-12 | The Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services | Immunotoxins, comprising an onc protein, directed against malignant cells |
US5859205A (en) | 1989-12-21 | 1999-01-12 | Celltech Limited | Humanised antibodies |
WO1999002567A2 (en) | 1997-07-08 | 1999-01-21 | Board Of Regents, The University Of Texas System | Compositions and methods for producing homoconjugates of antibodies which induce growth arrest or apoptosis of tumor cells |
US5874540A (en) | 1994-10-05 | 1999-02-23 | Immunomedics, Inc. | CDR-grafted type III anti-CEA humanized mouse monoclonal antibodies |
WO1999054440A1 (en) | 1998-04-21 | 1999-10-28 | Micromet Gesellschaft Für Biomedizinische Forschung Mbh | CD19xCD3 SPECIFIC POLYPEPTIDES AND USES THEREOF |
US6051230A (en) | 1992-03-05 | 2000-04-18 | Board Of Regents, The University Of Texas System | Compositions for targeting the vasculature of solid tumors |
US6051228A (en) | 1998-02-19 | 2000-04-18 | Bristol-Myers Squibb Co. | Antibodies against human CD40 |
US6056973A (en) | 1996-10-11 | 2000-05-02 | Sequus Pharmaceuticals, Inc. | Therapeutic liposome composition and method of preparation |
WO2000029584A1 (en) | 1998-11-18 | 2000-05-25 | Genentech, Inc. | Antibody variants with higher binding affinity compared to parent antibodies |
US6077499A (en) | 1996-05-03 | 2000-06-20 | Immunomedics, Inc. | Targeted combination immunotherapy of cancer |
US6096289A (en) | 1992-05-06 | 2000-08-01 | Immunomedics, Inc. | Intraoperative, intravascular, and endoscopic tumor and lesion detection, biopsy and therapy |
WO2000067796A1 (en) | 1999-05-07 | 2000-11-16 | Genentech, Inc. | Treatment of autoimmune diseases with antagonists which bind to b cell surface markers |
WO2000067795A1 (en) | 1999-05-10 | 2000-11-16 | Immunomedics, Inc. | Immunotherapy of b-cell malignancies using anti-cd22 antibodies |
US6156754A (en) | 1996-09-30 | 2000-12-05 | Bayer Aktiengesellschaft | Glycoconjugates of modified camptothecin derivatives (A-or B-ring linkage) |
WO2000074718A1 (en) | 1999-06-09 | 2000-12-14 | Immunomedics, Inc. | Immunotherapy of autoimmune disorders using antibodies which target b-cells |
WO2000076551A2 (en) | 1999-06-09 | 2000-12-21 | Ktb Tumorforschungs Gmbh | Method for producing an injectable medicament preparation |
US6165440A (en) | 1997-07-09 | 2000-12-26 | Board Of Regents, The University Of Texas System | Radiation and nanoparticles for enhancement of drug delivery in solid tumors |
US6201104B1 (en) | 1998-12-04 | 2001-03-13 | Entremed, Inc. | Angiogenesis—inhibiting protein binding peptides and proteins and methods of use |
US6214345B1 (en) | 1993-05-14 | 2001-04-10 | Bristol-Myers Squibb Co. | Lysosomal enzyme-cleavable antitumor drug conjugates |
WO2001024763A2 (en) | 1999-10-01 | 2001-04-12 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
US6254868B1 (en) | 1996-03-20 | 2001-07-03 | Immunomedics, Inc. | Glycosylated humanized B-cell specific antibodies |
US20010034363A1 (en) | 1996-03-12 | 2001-10-25 | Chun Li | Water soluble paclitaxel derivatives |
US6331175B1 (en) | 1985-07-05 | 2001-12-18 | Immunomedics, Inc. | Method and kit for imaging and treating organs and tissues |
US20020018749A1 (en) | 1997-03-27 | 2002-02-14 | Peter John Hudson | High avidity polyvalent and polyspecific reagents |
US6379698B1 (en) | 1999-04-06 | 2002-04-30 | Isis Pharmaceuticals, Inc. | Fusogenic lipids and vesicles |
US6416958B2 (en) | 1998-08-28 | 2002-07-09 | Dendreon Corporation | Selective apoptosis of neoplastic cells by an HLA-DR specific monoclonal antibody |
US6530944B2 (en) | 2000-02-08 | 2003-03-11 | Rice University | Optically-active nanoparticles for use in therapeutic and diagnostic methods |
US6562318B1 (en) | 1990-09-14 | 2003-05-13 | Syngenix Limited | Particular agents |
US20030103979A1 (en) | 1994-08-12 | 2003-06-05 | Leung Shui-On | Immunoconjugates and humanized antibodies specific for B-cell lymphoma and leukemia cells |
US20030133972A1 (en) | 2000-10-11 | 2003-07-17 | Targesome, Inc. | Targeted multivalent macromolecules |
WO2003070234A1 (en) | 2002-02-19 | 2003-08-28 | Case Western Reserve University | Alkylating agent combinations in the treatment of cancer |
US20030211498A1 (en) | 2000-04-03 | 2003-11-13 | Morin Patrice J | Tumor markers in ovarian cancer |
US6653104B2 (en) | 1996-10-17 | 2003-11-25 | Immunomedics, Inc. | Immunotoxins, comprising an internalizing antibody, directed against malignant and normal cells |
US20040001838A1 (en) | 2001-12-21 | 2004-01-01 | Immunogen, Inc. | Cytotoxic agents bearing a reactive polyethylene glycol moiety, cytotoxic conjugates comprising polyethylene glycol linking groups, and methods of making and using the same |
US20040076683A1 (en) | 2002-06-11 | 2004-04-22 | Ethypharm | Stealth lipid nanocapsules, methods for the preparation thereof, and use thereof as a carrier for active principle(s) |
US6730300B2 (en) | 1996-03-20 | 2004-05-04 | Immunomedics, Inc. | Humanization of an anti-carcinoembryonic antigen anti-idiotype antibody and use as a tumor vaccine and for targeting applications |
WO2004054622A1 (en) | 2002-12-13 | 2004-07-01 | Immunomedics, Inc. | Immunoconjugates with an intracellularly-cleavable linkage |
US20050013820A1 (en) | 2002-06-03 | 2005-01-20 | The Regents Of The University Of Michigan | Methods and compositions for the treatment of MHC-associated conditions |
US20050123540A1 (en) | 1999-11-08 | 2005-06-09 | Biogen Idec Inc. | Treatment of B cell malignancies using combination of B cell depleting antibody and immune modulating antibody related applications |
US7018809B1 (en) | 1991-09-19 | 2006-03-28 | Genentech, Inc. | Expression of functional antibody fragments |
US20060142506A1 (en) | 2004-10-25 | 2006-06-29 | Kurt Breitenkamp | Heterobifunctional poly(ethylene glycol) and uses thereof |
US20060193865A1 (en) | 2002-12-13 | 2006-08-31 | Immunomedics, Inc. | Camptothecin-binding moiety conjugates |
WO2006094192A2 (en) | 2005-03-03 | 2006-09-08 | Immunomedics, Inc. | Humanized l243 antibodies |
US7122636B1 (en) | 1997-02-21 | 2006-10-17 | Genentech, Inc. | Antibody fragment-polymer conjugates and uses of same |
US7151164B2 (en) | 2002-02-14 | 2006-12-19 | Immunomedics, Inc. | Anti-CD20 antibodies and fusion proteins thereof and methods of use |
US20070073047A1 (en) | 2002-06-10 | 2007-03-29 | Biogen Idec Ma Inc. | Genes overexpressed by ovarian cancer and their use in developing novel therapeutics |
US7238785B2 (en) | 2002-03-01 | 2007-07-03 | Immunomedics, Inc. | RS7 antibodies |
US7262278B2 (en) | 2001-10-15 | 2007-08-28 | Kirin Beer Kabushiki Kaisha | Anti-HLA-DR antibody |
WO2007123995A2 (en) | 2006-04-19 | 2007-11-01 | Bionumerik Pharmaceuticals, Inc. | Camptothecin-analog with a novel, “flipped” lactone-stable, e-ring and methods for making and using same |
US7312318B2 (en) | 2002-03-01 | 2007-12-25 | Immunomedics, Inc. | Internalizing anti-CD74 antibodies and methods of use |
US7387779B2 (en) | 1998-06-17 | 2008-06-17 | Beth Israel Deaconess Medical Center | Anti-angiogenic proteins and fragments and methods of use thereof |
US20080166363A1 (en) | 2002-12-13 | 2008-07-10 | Immunomedics, Inc. | Camptothecin-Binding Moiety Conjugates |
US7521056B2 (en) | 2005-04-06 | 2009-04-21 | Ibc Pharmaceuticals, Inc. | Stably tethered structures of defined compositions with multiple functions or binding specificities |
US7527787B2 (en) | 2005-10-19 | 2009-05-05 | Ibc Pharmaceuticals, Inc. | Multivalent immunoglobulin-based bioactive assemblies |
US7534866B2 (en) | 2005-10-19 | 2009-05-19 | Ibc Pharmaceuticals, Inc. | Methods and compositions for generating bioactive assemblies of increased complexity and uses |
US7550143B2 (en) | 2005-04-06 | 2009-06-23 | Ibc Pharmaceuticals, Inc. | Methods for generating stably linked complexes composed of homodimers, homotetramers or dimers of dimers and uses |
US20090202487A1 (en) | 2005-04-06 | 2009-08-13 | Ibc Pharmaceuticals, Inc. | Modular Method to Prepare Tetrameric Cytokines with Improved Pharmacokinetics by the Dock-and-Lock (DNL) Technology |
US20090300780A1 (en) | 2003-12-24 | 2009-12-03 | Lay Line Genomics S.P.A. | Method for the humanization of antibodies and humanized antibodies thereby obtained |
US7666400B2 (en) | 2005-04-06 | 2010-02-23 | Ibc Pharmaceuticals, Inc. | PEGylation by the dock and lock (DNL) technique |
US20100104589A1 (en) | 2002-12-13 | 2010-04-29 | Immunomedics, Inc. | Immunoconjugates with an Intracellularly-Cleavable Linkage |
WO2010089782A1 (en) | 2009-02-05 | 2010-08-12 | Saverio Alberti | Anti-trop-2 monoclonal antibodies and uses thereof in the treatment and diagnosis of tumors |
US20110070156A1 (en) | 2002-06-14 | 2011-03-24 | Immunomedics, Inc. | Combining Radioimmunotherapy and Antibody-Drug Conjugates for Improved Cancer Therapy |
US20110160159A1 (en) | 2009-09-15 | 2011-06-30 | John Ryan | Treatment of cancer |
US20110171126A1 (en) | 2010-01-11 | 2011-07-14 | Center For Molecular Medicine And Immunology | Enhanced Cytotoxicity of Anti-CD74 and Anti-HLA-DR Antibodies with Interferon-Gamma |
US20110256053A1 (en) | 2005-04-06 | 2011-10-20 | Immunomedics, Inc. | Multiple Signaling Pathways Induced by Hexavalent, Monospecific and Bispecific Antibodies for Enhanced Toxicity to B-Cell Lymphomas and Other Diseases |
US20110274704A1 (en) | 2004-02-13 | 2011-11-10 | Ibc Pharmaceuticals, Inc. | Compositions and Methods of Use of Immunotoxins Comprising Ranpirnase (Rap) Show Potent Cytotoxic Activity |
US20110305631A1 (en) | 2002-12-13 | 2011-12-15 | Immunomedics, Inc. | Camptothecin Conjugates of Anti-CD22 Antibodies for Treatment of B Cell Diseases |
US8119101B2 (en) | 1999-05-10 | 2012-02-21 | The Ohio State University | Anti-CD74 immunoconjugates and methods of use |
WO2012151199A1 (en) | 2011-05-02 | 2012-11-08 | Immunomedics, Inc. | Ultrafiltration concentration of allotype selected antibodies for small-volume administration |
US8309094B2 (en) | 2011-04-01 | 2012-11-13 | Wyeth Llc | Antibody-drug conjugates |
US20130089872A1 (en) | 2010-05-17 | 2013-04-11 | Livtech, Inc. | Anti-human trop-2 antibody having anti-tumor activity in vivo |
US20130122020A1 (en) | 2011-11-11 | 2013-05-16 | Rinat Neuroscience Corp. | Antibodies specific for trop-2 and their uses |
US20140099254A1 (en) | 2012-08-14 | 2014-04-10 | Ibc Pharmaceuticals, Inc. | Combination therapy for inducing immune response to disease |
US20140219914A1 (en) | 2012-12-13 | 2014-08-07 | Immunomedics, Inc. | Dosages of Immunoconjugates of Antibodies and SN-38 for Improved Efficacy and Decreased Toxicity |
WO2014124227A1 (en) | 2013-02-07 | 2014-08-14 | Immunomedics, Inc. | Pro-drug form (p2pdox) of the highly potent 2-pyrrolinodoxorubicin conjugated to antibodies for targeted therapy of cancer |
US8913903B2 (en) | 2012-01-05 | 2014-12-16 | Brother Kogyo Kabushiki Kaisha | Image forming apparatus capable of electrically detecting usage state of process cartridge mounted therein |
WO2015047510A1 (en) | 2013-09-27 | 2015-04-02 | Immunomedics, Inc. | Anti-trop-2 antibody-drug conjugates and uses thereof |
US20150118222A1 (en) | 2013-10-25 | 2015-04-30 | Pharmacyclics, Inc. | Treatment using bruton's tyrosine kinase inhibitors and immunotherapy |
WO2015069430A2 (en) | 2013-11-05 | 2015-05-14 | Immunomedics, Inc. | Humanized anti-ceacam5 antibody and uses thereof |
US20160000915A1 (en) | 2011-12-05 | 2016-01-07 | Immunomedics, Inc. | Crosslinking of cd22 by epratuzumab triggers bcr signaling and caspase-dependent apoptosis in hematopoietic cancer cells |
WO2016028896A1 (en) | 2014-08-19 | 2016-02-25 | Novartis Ag | Anti-cd123 chimeric antigen receptor (car) for use in cancer treatment |
US20160095939A1 (en) | 2014-10-07 | 2016-04-07 | Immunomedics, Inc. | Neoadjuvant use of antibody-drug conjugates |
US9492566B2 (en) | 2012-12-13 | 2016-11-15 | Immunomedics, Inc. | Antibody-drug conjugates and uses thereof |
WO2016210108A1 (en) | 2015-06-25 | 2016-12-29 | Immunomedics, Inc. | Combining anti-hla-dr or anti-trop-2 antibodies with microtubule inhibitors, parp inhibitors, bruton kinase inhibitors or phosphoinositide 3-kinase inhibitors significantly improves therapeutic outcome in cancer |
US10058621B2 (en) * | 2015-06-25 | 2018-08-28 | Immunomedics, Inc. | Combination therapy with anti-HLA-DR antibodies and kinase inhibitors in hematopoietic cancers |
US10206918B2 (en) * | 2012-12-13 | 2019-02-19 | Immunomedics, Inc. | Efficacy of anti-HLA-DR antiboddy drug conjugate IMMU-140 (hL243-CL2A-SN-38) in HLA-DR positive cancers |
-
2017
- 2017-04-11 US US15/484,308 patent/US10058621B2/en active Active
-
2018
- 2018-07-20 US US16/041,399 patent/US10988539B2/en active Active
Patent Citations (207)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4046722A (en) | 1975-02-04 | 1977-09-06 | G. D. Searle & Co. Limited | Immunological materials |
US4036945A (en) | 1976-05-03 | 1977-07-19 | The Massachusetts General Hospital | Composition and method for determining the size and location of myocardial infarcts |
US4200690A (en) | 1976-12-16 | 1980-04-29 | Millipore Corporation | Immunoassay with membrane immobilized antibody |
US4331647A (en) | 1980-03-03 | 1982-05-25 | Goldenberg Milton David | Tumor localization and therapy with labeled antibody fragments specific to tumor-associated markers |
US5204095A (en) | 1980-04-09 | 1993-04-20 | National Research Development Corporation | Monoclonal antibodies against hepatitis B virus |
US4359457A (en) | 1980-09-30 | 1982-11-16 | Neville Jr David M | Anti Thy 1.2 monoclonal antibody-ricin hybrid utilized as a tumor suppressant |
US4916213A (en) | 1983-02-22 | 1990-04-10 | Xoma Corporation | Ribosomal inhibiting protein-immunoglobulin conjugates with specificity for tumor cell surface antigens, and mixtures thereof |
US4925922A (en) | 1983-02-22 | 1990-05-15 | Xoma Corporation | Potentiation of cytotoxic conjugates |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US5795967A (en) | 1984-07-05 | 1998-08-18 | Genentech, Inc. | Tumor necrosis factor antagonists and their use |
US4824659A (en) | 1985-06-07 | 1989-04-25 | Immunomedics, Inc. | Antibody conjugates |
US6331175B1 (en) | 1985-07-05 | 2001-12-18 | Immunomedics, Inc. | Method and kit for imaging and treating organs and tissues |
US4918163B1 (en) | 1985-09-27 | 1993-08-17 | Univ California | |
US4918163A (en) | 1985-09-27 | 1990-04-17 | Pfizer Inc. | Monoclonal antibodies specific for lipid-A determinants of gram negative bacteria |
US5618920A (en) | 1985-11-01 | 1997-04-08 | Xoma Corporation | Modular assembly of antibody genes, antibodies prepared thereby and use |
US4699784A (en) | 1986-02-25 | 1987-10-13 | Center For Molecular Medicine & Immunology | Tumoricidal methotrexate-antibody conjugate |
US5057313A (en) | 1986-02-25 | 1991-10-15 | The Center For Molecular Medicine And Immunology | Diagnostic and therapeutic antibody conjugates |
EP0253202A2 (en) | 1986-06-30 | 1988-01-20 | Oncogen | Novel immunoconjugates and methods for their use in tumor therapy |
US4704692A (en) | 1986-09-02 | 1987-11-03 | Ladner Robert C | Computer based system and method for determining and displaying possible chemical structures for converting double- or multiple-chain polypeptides to single-chain polypeptides |
US5567610A (en) | 1986-09-04 | 1996-10-22 | Bioinvent International Ab | Method of producing human monoclonal antibodies and kit therefor |
US5817307A (en) | 1986-11-06 | 1998-10-06 | The Texas A&M University System | Treatment of bacterial infection with oral interferon-α |
US4932412A (en) | 1986-12-18 | 1990-06-12 | Immunomedics, Inc. | Intraoperative and endoscopic tumor detection and therapy |
US5106955A (en) | 1987-03-26 | 1992-04-21 | Teijin Limited | Process for preparation of antibody conjugates |
EP0306943A2 (en) | 1987-09-10 | 1989-03-15 | Neorx Corporation | Immunconjugates joined by thioether bonds having reduced toxicity and improved selectivity |
US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
US5122368A (en) | 1988-02-11 | 1992-06-16 | Bristol-Myers Squibb Company | Anthracycline conjugates having a novel linker and methods for their production |
US5112954A (en) | 1988-02-26 | 1992-05-12 | Neorx Corporation | Method of enhancing the effect of cytotoxic agents |
EP0332865A2 (en) | 1988-03-17 | 1989-09-20 | American Cyanamid Company | Suppression of B-cells in mammals |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US6180370B1 (en) | 1988-12-28 | 2001-01-30 | Protein Design Labs, Inc. | Humanized immunoglobulins and methods of making the same |
US5585089A (en) | 1988-12-28 | 1996-12-17 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US7022500B1 (en) | 1988-12-28 | 2006-04-04 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5693762A (en) | 1988-12-28 | 1997-12-02 | Protein Design Labs, Inc. | Humanized immunoglobulins |
WO1990009196A1 (en) | 1989-02-10 | 1990-08-23 | Celltech Limited | Cross-linked antibodies and processes for their preparation |
US5134075A (en) | 1989-02-17 | 1992-07-28 | Oncogen Limited Partnership | Monoclonal antibody to novel antigen associated with human tumors |
US5171665A (en) | 1989-04-17 | 1992-12-15 | Oncogen | Monoclonal antibody to novel antigen associated with human tumors |
US5196337A (en) | 1989-04-24 | 1993-03-23 | Sumitomo Chemical Company, Limited | Human monoclonal antibody, and its production and use |
US5859205A (en) | 1989-12-21 | 1999-01-12 | Celltech Limited | Humanised antibodies |
WO1991011465A1 (en) | 1990-01-26 | 1991-08-08 | Immunomedics, Inc. | Vaccines against cancer and infectious diseases |
WO1991013974A1 (en) | 1990-03-14 | 1991-09-19 | The Biomembrane Institute | Monoclonal antibody and immunoconjugates for the treatment and detection of b cell disorders |
US5229275A (en) | 1990-04-26 | 1993-07-20 | Akzo N.V. | In-vitro method for producing antigen-specific human monoclonal antibodies |
US5633425A (en) | 1990-08-29 | 1997-05-27 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US6562318B1 (en) | 1990-09-14 | 2003-05-13 | Syngenix Limited | Particular agents |
US5679640A (en) | 1991-02-12 | 1997-10-21 | Cytel Corporation | Immunosuppressant peptides |
EP0510949A2 (en) | 1991-04-23 | 1992-10-28 | Sangstat Medical Corporation | Cytomodulating conjugates of members of specific binding pairs |
US5750105A (en) | 1991-07-25 | 1998-05-12 | Idec Pharmaceuticals Corporation | Recombinant antibodies for human therapy |
US7018809B1 (en) | 1991-09-19 | 2006-03-28 | Genentech, Inc. | Expression of functional antibody fragments |
US5708146A (en) | 1992-01-23 | 1998-01-13 | Bristol-Myers Squibb Company | Thioether conjugates |
US6051230A (en) | 1992-03-05 | 2000-04-18 | Board Of Regents, The University Of Texas System | Compositions for targeting the vasculature of solid tumors |
US6096289A (en) | 1992-05-06 | 2000-08-01 | Immunomedics, Inc. | Intraoperative, intravascular, and endoscopic tumor and lesion detection, biopsy and therapy |
US6387350B2 (en) | 1992-05-06 | 2002-05-14 | Immunomedics, Inc. | Intraoperative, intravascular and endoscopic tumor and lesion detection, biopsy and therapy |
US5716595A (en) | 1992-05-06 | 1998-02-10 | Immunomedics, Inc. | Intraperative, intravascular and endoscopic tumor and lesion detection and therapy with monovalent antibody fragments |
US5686072A (en) | 1992-06-17 | 1997-11-11 | Board Of Regents, The University Of Texas | Epitope-specific monoclonal antibodies and immunotoxins and uses thereof |
US5525338A (en) | 1992-08-21 | 1996-06-11 | Immunomedics, Inc. | Detection and therapy of lesions with biotin/avidin conjugates |
US5776456A (en) | 1992-11-13 | 1998-07-07 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
US5792852A (en) | 1992-11-16 | 1998-08-11 | Cancer Research Fund Of Contra Costa | Polynucleotides encoding modified antibodies with human milk fat globule specificity |
US5620708A (en) | 1993-02-22 | 1997-04-15 | Alza Corporation | Compositions and methods for the oral delivery of active agents |
US5702727A (en) | 1993-02-22 | 1997-12-30 | Alza Corporation | Compositions and methods for the oral delivery of active agents |
US6214345B1 (en) | 1993-05-14 | 2001-04-10 | Bristol-Myers Squibb Co. | Lysosomal enzyme-cleavable antitumor drug conjugates |
US5922302A (en) | 1993-05-17 | 1999-07-13 | Immunomedics, Inc. | Detection and therapy of lesions with biotin/avidin-metal chelating protein conjugates |
US5736119A (en) | 1993-05-17 | 1998-04-07 | Immunomedics, Inc. | Detection and therapy of lesions with biotin/avidin-metal chelating protein conjugates |
US5484892A (en) | 1993-05-21 | 1996-01-16 | Dana-Farber Cancer Institute, Inc. | Monoclonal antibodies that block ligand binding to the CD22 receptor in mature B cells |
WO1994027638A1 (en) | 1993-05-21 | 1994-12-08 | Dana-Farber Cancer Institute, Inc. | Monoclonal antibodies that block ligand binding to the cd22 receptor in mature b cells |
US6180377B1 (en) | 1993-06-16 | 2001-01-30 | Celltech Therapeutics Limited | Humanized antibodies |
WO1994029451A2 (en) | 1993-06-16 | 1994-12-22 | Celltech Limited | Humanised antibodies |
US5565215A (en) | 1993-07-23 | 1996-10-15 | Massachusettes Institute Of Technology | Biodegradable injectable particles for imaging |
US5593676A (en) | 1993-08-02 | 1997-01-14 | The Leland Stanford Junior University | Method of killing B cells using antibodies which bind CDIM |
WO1995009917A1 (en) | 1993-10-07 | 1995-04-13 | The Regents Of The University Of California | Genetically engineered bispecific tetravalent antibodies |
US5824701A (en) | 1993-10-20 | 1998-10-20 | Enzon, Inc. | Taxane-based prodrugs |
US5443953A (en) | 1993-12-08 | 1995-08-22 | Immunomedics, Inc. | Preparation and use of immunoconjugates |
US5792845A (en) | 1994-04-26 | 1998-08-11 | The Children's Medical Center Corporation | Nucleotides encoding angiostatin protein and method of use |
US5698178A (en) | 1994-08-05 | 1997-12-16 | Immunomedics, Inc. | Polyspecific immunoconjugates and antibody composites for targeting the multidrug resistant phenotype |
US5789554A (en) | 1994-08-12 | 1998-08-04 | Immunomedics, Inc. | Immunoconjugates and humanized antibodies specific for B-cell lymphoma and leukemia cells |
US20030103979A1 (en) | 1994-08-12 | 2003-06-05 | Leung Shui-On | Immunoconjugates and humanized antibodies specific for B-cell lymphoma and leukemia cells |
US6187287B1 (en) | 1994-08-12 | 2001-02-13 | Immunomedics, Inc. | Immunoconjugates and humanized antibodies specific for B-cell lymphoma and leukemia cells |
WO1996004925A1 (en) | 1994-08-12 | 1996-02-22 | Immunomedics, Inc. | Immunoconjugates and humanized antibodies specific for b-cell lymphoma and leukemia cells |
US5874540A (en) | 1994-10-05 | 1999-02-23 | Immunomedics, Inc. | CDR-grafted type III anti-CEA humanized mouse monoclonal antibodies |
US5798554A (en) | 1995-02-24 | 1998-08-25 | Consorzio Per La Ricerca Sulla Microelettronica Nel Mezzogiorno | MOS-technology power device integrated structure and manufacturing process thereof |
US20010034363A1 (en) | 1996-03-12 | 2001-10-25 | Chun Li | Water soluble paclitaxel derivatives |
US6254868B1 (en) | 1996-03-20 | 2001-07-03 | Immunomedics, Inc. | Glycosylated humanized B-cell specific antibodies |
US6730300B2 (en) | 1996-03-20 | 2004-05-04 | Immunomedics, Inc. | Humanization of an anti-carcinoembryonic antigen anti-idiotype antibody and use as a tumor vaccine and for targeting applications |
US6077499A (en) | 1996-05-03 | 2000-06-20 | Immunomedics, Inc. | Targeted combination immunotherapy of cancer |
WO1998004281A1 (en) | 1996-07-26 | 1998-02-05 | Smithkline Beecham Corpration | Improved method of treating immune cell mediated systemic diseases |
US6156754A (en) | 1996-09-30 | 2000-12-05 | Bayer Aktiengesellschaft | Glycoconjugates of modified camptothecin derivatives (A-or B-ring linkage) |
US6056973A (en) | 1996-10-11 | 2000-05-02 | Sequus Pharmaceuticals, Inc. | Therapeutic liposome composition and method of preparation |
US6653104B2 (en) | 1996-10-17 | 2003-11-25 | Immunomedics, Inc. | Immunotoxins, comprising an internalizing antibody, directed against malignant and normal cells |
US7122636B1 (en) | 1997-02-21 | 2006-10-17 | Genentech, Inc. | Antibody fragment-polymer conjugates and uses of same |
US7910103B2 (en) | 1997-03-24 | 2011-03-22 | Immunomedics, Inc. | Immunotherapy of B-cell malignancies using anti-CD22 antibodies |
US6306393B1 (en) | 1997-03-24 | 2001-10-23 | Immunomedics, Inc. | Immunotherapy of B-cell malignancies using anti-CD22 antibodies |
WO1998042378A1 (en) | 1997-03-24 | 1998-10-01 | Immunomedics, Inc. | Immunotherapy of b-cell malignancies using anti-cd22 antibodies |
US6183744B1 (en) | 1997-03-24 | 2001-02-06 | Immunomedics, Inc. | Immunotherapy of B-cell malignancies using anti-CD22 antibodies |
US20020018749A1 (en) | 1997-03-27 | 2002-02-14 | Peter John Hudson | High avidity polyvalent and polyspecific reagents |
US6395276B1 (en) | 1997-05-02 | 2002-05-28 | Immunomedics, Inc. | Immunotoxins directed against malignant cells |
WO1998050435A1 (en) | 1997-05-02 | 1998-11-12 | The Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services | Immunotoxins, comprising an onc protein, directed against malignant cells |
WO1999002567A2 (en) | 1997-07-08 | 1999-01-21 | Board Of Regents, The University Of Texas System | Compositions and methods for producing homoconjugates of antibodies which induce growth arrest or apoptosis of tumor cells |
US6165440A (en) | 1997-07-09 | 2000-12-26 | Board Of Regents, The University Of Texas System | Radiation and nanoparticles for enhancement of drug delivery in solid tumors |
US6051228A (en) | 1998-02-19 | 2000-04-18 | Bristol-Myers Squibb Co. | Antibodies against human CD40 |
WO1999054440A1 (en) | 1998-04-21 | 1999-10-28 | Micromet Gesellschaft Für Biomedizinische Forschung Mbh | CD19xCD3 SPECIFIC POLYPEPTIDES AND USES THEREOF |
US7387779B2 (en) | 1998-06-17 | 2008-06-17 | Beth Israel Deaconess Medical Center | Anti-angiogenic proteins and fragments and methods of use thereof |
US6416958B2 (en) | 1998-08-28 | 2002-07-09 | Dendreon Corporation | Selective apoptosis of neoplastic cells by an HLA-DR specific monoclonal antibody |
WO2000029584A1 (en) | 1998-11-18 | 2000-05-25 | Genentech, Inc. | Antibody variants with higher binding affinity compared to parent antibodies |
US6201104B1 (en) | 1998-12-04 | 2001-03-13 | Entremed, Inc. | Angiogenesis—inhibiting protein binding peptides and proteins and methods of use |
US6379698B1 (en) | 1999-04-06 | 2002-04-30 | Isis Pharmaceuticals, Inc. | Fusogenic lipids and vesicles |
WO2000067796A1 (en) | 1999-05-07 | 2000-11-16 | Genentech, Inc. | Treatment of autoimmune diseases with antagonists which bind to b cell surface markers |
US7820161B1 (en) | 1999-05-07 | 2010-10-26 | Biogen Idec, Inc. | Treatment of autoimmune diseases |
US8119101B2 (en) | 1999-05-10 | 2012-02-21 | The Ohio State University | Anti-CD74 immunoconjugates and methods of use |
WO2000067795A1 (en) | 1999-05-10 | 2000-11-16 | Immunomedics, Inc. | Immunotherapy of b-cell malignancies using anti-cd22 antibodies |
WO2000076551A2 (en) | 1999-06-09 | 2000-12-21 | Ktb Tumorforschungs Gmbh | Method for producing an injectable medicament preparation |
WO2000074718A1 (en) | 1999-06-09 | 2000-12-14 | Immunomedics, Inc. | Immunotherapy of autoimmune disorders using antibodies which target b-cells |
US7074403B1 (en) | 1999-06-09 | 2006-07-11 | Immunomedics, Inc. | Immunotherapy of autoimmune disorders using antibodies which target B-cells |
WO2001024763A2 (en) | 1999-10-01 | 2001-04-12 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
US20050123540A1 (en) | 1999-11-08 | 2005-06-09 | Biogen Idec Inc. | Treatment of B cell malignancies using combination of B cell depleting antibody and immune modulating antibody related applications |
US6530944B2 (en) | 2000-02-08 | 2003-03-11 | Rice University | Optically-active nanoparticles for use in therapeutic and diagnostic methods |
US20030211498A1 (en) | 2000-04-03 | 2003-11-13 | Morin Patrice J | Tumor markers in ovarian cancer |
US20030133972A1 (en) | 2000-10-11 | 2003-07-17 | Targesome, Inc. | Targeted multivalent macromolecules |
US7262278B2 (en) | 2001-10-15 | 2007-08-28 | Kirin Beer Kabushiki Kaisha | Anti-HLA-DR antibody |
US6716821B2 (en) | 2001-12-21 | 2004-04-06 | Immunogen Inc. | Cytotoxic agents bearing a reactive polyethylene glycol moiety, cytotoxic conjugates comprising polyethylene glycol linking groups, and methods of making and using the same |
US20040001838A1 (en) | 2001-12-21 | 2004-01-01 | Immunogen, Inc. | Cytotoxic agents bearing a reactive polyethylene glycol moiety, cytotoxic conjugates comprising polyethylene glycol linking groups, and methods of making and using the same |
US7151164B2 (en) | 2002-02-14 | 2006-12-19 | Immunomedics, Inc. | Anti-CD20 antibodies and fusion proteins thereof and methods of use |
WO2003070234A1 (en) | 2002-02-19 | 2003-08-28 | Case Western Reserve University | Alkylating agent combinations in the treatment of cancer |
US7238785B2 (en) | 2002-03-01 | 2007-07-03 | Immunomedics, Inc. | RS7 antibodies |
US7931903B2 (en) | 2002-03-01 | 2011-04-26 | Immunomedics, Inc. | Internalizing anti-CD74 antibodies and methods of use |
US20070212350A1 (en) | 2002-03-01 | 2007-09-13 | Immunomedics, Inc. | Rs7 antibodies |
US7772373B2 (en) | 2002-03-01 | 2010-08-10 | Immunomedics, Inc. | Internalizing anti-CD74 antibodies and methods of use |
US7312318B2 (en) | 2002-03-01 | 2007-12-25 | Immunomedics, Inc. | Internalizing anti-CD74 antibodies and methods of use |
US8084583B2 (en) | 2002-03-01 | 2011-12-27 | Immunomedics, Inc. | RS7 antibodies |
US7517964B2 (en) | 2002-03-01 | 2009-04-14 | Immunomedics, Inc. | RS7 antibodies |
US20050013820A1 (en) | 2002-06-03 | 2005-01-20 | The Regents Of The University Of Michigan | Methods and compositions for the treatment of MHC-associated conditions |
US20070073047A1 (en) | 2002-06-10 | 2007-03-29 | Biogen Idec Ma Inc. | Genes overexpressed by ovarian cancer and their use in developing novel therapeutics |
US20040076683A1 (en) | 2002-06-11 | 2004-04-22 | Ethypharm | Stealth lipid nanocapsules, methods for the preparation thereof, and use thereof as a carrier for active principle(s) |
US20110070156A1 (en) | 2002-06-14 | 2011-03-24 | Immunomedics, Inc. | Combining Radioimmunotherapy and Antibody-Drug Conjugates for Improved Cancer Therapy |
US8425912B2 (en) | 2002-12-13 | 2013-04-23 | Immunomedics, Inc. | Immunoconjugates with an intracellularly-cleavable linkage |
US7999083B2 (en) | 2002-12-13 | 2011-08-16 | Immunomedics, Inc. | Immunoconjugates with an intracellularly-cleavable linkage |
US20130090458A1 (en) | 2002-12-13 | 2013-04-11 | Immunomedics, Inc. | Immunoconjugates with an Intracellularly-Cleavable Linkage |
US20120328564A1 (en) | 2002-12-13 | 2012-12-27 | Immunomedics, Inc. | Camptothecin-Binding Moiety Conjugates |
US8268319B2 (en) | 2002-12-13 | 2012-09-18 | Immunomedics, Inc. | Immunoconjugates with an intracellularly-cleavable linkage |
US7585491B2 (en) | 2002-12-13 | 2009-09-08 | Immunomedics, Inc. | Immunoconjugates with an intracellularly-cleavable linkage |
US7591994B2 (en) | 2002-12-13 | 2009-09-22 | Immunomedics, Inc. | Camptothecin-binding moiety conjugates |
US8268317B2 (en) | 2002-12-13 | 2012-09-18 | Immunomedics, Inc. | Camptothecin-binding moiety conjugates |
US20120082617A1 (en) | 2002-12-13 | 2012-04-05 | Immunomedics, Inc. | Immunoconjugates with an Intracellularly-Cleavable Linkage |
US8420086B2 (en) | 2002-12-13 | 2013-04-16 | Immunomedics, Inc. | Camptothecin conjugates of anti-CD22 antibodies for treatment of B cell diseases |
US20100104589A1 (en) | 2002-12-13 | 2010-04-29 | Immunomedics, Inc. | Immunoconjugates with an Intracellularly-Cleavable Linkage |
US20080166363A1 (en) | 2002-12-13 | 2008-07-10 | Immunomedics, Inc. | Camptothecin-Binding Moiety Conjugates |
US8080250B1 (en) | 2002-12-13 | 2011-12-20 | Immunomedics, Inc. | Immunoconjugates with an intracellularly-cleavable linkage |
US20130177526A1 (en) | 2002-12-13 | 2013-07-11 | Immunomedics, Inc. | Camptothecin Conjugates of Anti-CD22 Antibodies for Treatment of B Cell Diseases |
US20110305631A1 (en) | 2002-12-13 | 2011-12-15 | Immunomedics, Inc. | Camptothecin Conjugates of Anti-CD22 Antibodies for Treatment of B Cell Diseases |
WO2004054622A1 (en) | 2002-12-13 | 2004-07-01 | Immunomedics, Inc. | Immunoconjugates with an intracellularly-cleavable linkage |
US20130216561A1 (en) | 2002-12-13 | 2013-08-22 | Immunomedics, Inc. | Immunoconjugates with an Intracellularly-Cleavable Linkage |
US20140004078A1 (en) | 2002-12-13 | 2014-01-02 | Immunomedics, Inc. | Immunoconjugates with an Intracellularly-Cleavable Linkage |
US20060193865A1 (en) | 2002-12-13 | 2006-08-31 | Immunomedics, Inc. | Camptothecin-binding moiety conjugates |
US20090300780A1 (en) | 2003-12-24 | 2009-12-03 | Lay Line Genomics S.P.A. | Method for the humanization of antibodies and humanized antibodies thereby obtained |
US20110274704A1 (en) | 2004-02-13 | 2011-11-10 | Ibc Pharmaceuticals, Inc. | Compositions and Methods of Use of Immunotoxins Comprising Ranpirnase (Rap) Show Potent Cytotoxic Activity |
US20060142506A1 (en) | 2004-10-25 | 2006-06-29 | Kurt Breitenkamp | Heterobifunctional poly(ethylene glycol) and uses thereof |
US8992917B2 (en) | 2005-03-03 | 2015-03-31 | Immunomedics, Inc. | Humanized L243 antibodies |
US8722047B2 (en) | 2005-03-03 | 2014-05-13 | Immunomedics, Inc. | Humanized anti-HLA-DR antibodies |
US20150166659A1 (en) | 2005-03-03 | 2015-06-18 | Immunomedics, Inc. | Humanized L243 Antibodies |
US20100196267A1 (en) | 2005-03-03 | 2010-08-05 | Immunomedics, Inc. | Humanized L243 Antibodies |
US20100196266A1 (en) | 2005-03-03 | 2010-08-05 | Immunomedics, Inc. | Humanized Anti-HLA-DR Antibodies |
WO2006094192A2 (en) | 2005-03-03 | 2006-09-08 | Immunomedics, Inc. | Humanized l243 antibodies |
US8613903B2 (en) | 2005-03-03 | 2013-12-24 | Immunomedics, Inc. | Humanized L243 antibodies |
US9187561B2 (en) | 2005-03-03 | 2015-11-17 | Immunomedics, Inc. | Humanized anti-HLA-DR antibodies |
US7612180B2 (en) | 2005-03-03 | 2009-11-03 | Immunomedics, Inc. | Humanized L243 antibodies |
US20060210475A1 (en) | 2005-03-03 | 2006-09-21 | Goldenberg David M | Humanized L243 antibodies |
US20160024212A1 (en) | 2005-03-03 | 2016-01-28 | Immunomedics, Inc. | Humanized Anti-HLA-DR Antibodies |
US7666400B2 (en) | 2005-04-06 | 2010-02-23 | Ibc Pharmaceuticals, Inc. | PEGylation by the dock and lock (DNL) technique |
US7550143B2 (en) | 2005-04-06 | 2009-06-23 | Ibc Pharmaceuticals, Inc. | Methods for generating stably linked complexes composed of homodimers, homotetramers or dimers of dimers and uses |
US20110256053A1 (en) | 2005-04-06 | 2011-10-20 | Immunomedics, Inc. | Multiple Signaling Pathways Induced by Hexavalent, Monospecific and Bispecific Antibodies for Enhanced Toxicity to B-Cell Lymphomas and Other Diseases |
US7521056B2 (en) | 2005-04-06 | 2009-04-21 | Ibc Pharmaceuticals, Inc. | Stably tethered structures of defined compositions with multiple functions or binding specificities |
US20090202487A1 (en) | 2005-04-06 | 2009-08-13 | Ibc Pharmaceuticals, Inc. | Modular Method to Prepare Tetrameric Cytokines with Improved Pharmacokinetics by the Dock-and-Lock (DNL) Technology |
US7534866B2 (en) | 2005-10-19 | 2009-05-19 | Ibc Pharmaceuticals, Inc. | Methods and compositions for generating bioactive assemblies of increased complexity and uses |
US7527787B2 (en) | 2005-10-19 | 2009-05-05 | Ibc Pharmaceuticals, Inc. | Multivalent immunoglobulin-based bioactive assemblies |
WO2007123995A2 (en) | 2006-04-19 | 2007-11-01 | Bionumerik Pharmaceuticals, Inc. | Camptothecin-analog with a novel, “flipped” lactone-stable, e-ring and methods for making and using same |
US20120052076A1 (en) | 2009-02-05 | 2012-03-01 | Saverio Alberti | Anti-trop-2 monoclonal antibodies and uses thereof in the treatment and diagnosis of tumors |
WO2010089782A1 (en) | 2009-02-05 | 2010-08-12 | Saverio Alberti | Anti-trop-2 monoclonal antibodies and uses thereof in the treatment and diagnosis of tumors |
US20110160159A1 (en) | 2009-09-15 | 2011-06-30 | John Ryan | Treatment of cancer |
US20110171126A1 (en) | 2010-01-11 | 2011-07-14 | Center For Molecular Medicine And Immunology | Enhanced Cytotoxicity of Anti-CD74 and Anti-HLA-DR Antibodies with Interferon-Gamma |
US20130089872A1 (en) | 2010-05-17 | 2013-04-11 | Livtech, Inc. | Anti-human trop-2 antibody having anti-tumor activity in vivo |
US8309094B2 (en) | 2011-04-01 | 2012-11-13 | Wyeth Llc | Antibody-drug conjugates |
US8586049B2 (en) | 2011-04-01 | 2013-11-19 | Wyeth Llc | Antibody-drug conjugates |
US20140178294A1 (en) | 2011-05-02 | 2014-06-26 | Immunomedics, Inc. | Ultrafiltration Concentration of Allotype Selected Antibodies for Small-Volume Administration |
US8658773B2 (en) | 2011-05-02 | 2014-02-25 | Immunomedics, Inc. | Ultrafiltration concentration of allotype selected antibodies for small-volume administration |
US20160032008A1 (en) | 2011-05-02 | 2016-02-04 | Immunomedics, Inc. | Stable Compositions of High-Concentration Allotype-Selected Antibodies for Small-Volume Administration |
US9468689B2 (en) | 2011-05-02 | 2016-10-18 | Immunomedics, Inc. | Ultrafiltration concentration of allotype selected antibodies for small-volume administration |
WO2012151199A1 (en) | 2011-05-02 | 2012-11-08 | Immunomedics, Inc. | Ultrafiltration concentration of allotype selected antibodies for small-volume administration |
US9180205B2 (en) | 2011-05-02 | 2015-11-10 | Immunomedics, Inc. | Stable compositions of high-concentration allotype-selected antibodies for small-volume administration |
US8871908B2 (en) | 2011-11-11 | 2014-10-28 | Rinat Neuroscience Corp. | Antibodies specific for Trop-2 and their uses |
US20130122020A1 (en) | 2011-11-11 | 2013-05-16 | Rinat Neuroscience Corp. | Antibodies specific for trop-2 and their uses |
US20160000915A1 (en) | 2011-12-05 | 2016-01-07 | Immunomedics, Inc. | Crosslinking of cd22 by epratuzumab triggers bcr signaling and caspase-dependent apoptosis in hematopoietic cancer cells |
US8913903B2 (en) | 2012-01-05 | 2014-12-16 | Brother Kogyo Kabushiki Kaisha | Image forming apparatus capable of electrically detecting usage state of process cartridge mounted therein |
US20140099254A1 (en) | 2012-08-14 | 2014-04-10 | Ibc Pharmaceuticals, Inc. | Combination therapy for inducing immune response to disease |
US9493573B2 (en) * | 2012-12-13 | 2016-11-15 | Immunomedics, Inc. | Dosages of immunoconjugates of antibodies and SN-38 for improved efficacy and decreased toxicity |
US9028833B2 (en) | 2012-12-13 | 2015-05-12 | Immunomedics, Inc. | Dosages of immunoconjugates of antibodies and SN-38 for improved efficacy and decreased toxicity |
US9522959B2 (en) * | 2012-12-13 | 2016-12-20 | Immunomedics, Inc. | Dosages of immunoconjugates of antibodies and SN-38 for improved efficacy and decreased toxicity |
US10206918B2 (en) * | 2012-12-13 | 2019-02-19 | Immunomedics, Inc. | Efficacy of anti-HLA-DR antiboddy drug conjugate IMMU-140 (hL243-CL2A-SN-38) in HLA-DR positive cancers |
US10709701B2 (en) * | 2012-12-13 | 2020-07-14 | Immunomedics, Inc. | Efficacy of anti-HLA-DR antibody drug conjugate IMMU-140 (hL243-CL2A-SN-38) in HLA-DR positive cancers |
US9492566B2 (en) | 2012-12-13 | 2016-11-15 | Immunomedics, Inc. | Antibody-drug conjugates and uses thereof |
US20140219914A1 (en) | 2012-12-13 | 2014-08-07 | Immunomedics, Inc. | Dosages of Immunoconjugates of Antibodies and SN-38 for Improved Efficacy and Decreased Toxicity |
US9486536B2 (en) | 2013-02-07 | 2016-11-08 | Immunomedics, Inc. | Pro-drug form (P2PDOX) of the highly potent 2-pyrrolinodoxorubicin conjugated to antibodies for targeted therapy of cancer |
US9694088B2 (en) | 2013-02-07 | 2017-07-04 | Immunomedics, Inc. | Pro-drug form (P2PDox) of the highly potent 2-pyrrolinodoxorubicin conjugated to antibodies for targeted therapy of cancer |
WO2014124227A1 (en) | 2013-02-07 | 2014-08-14 | Immunomedics, Inc. | Pro-drug form (p2pdox) of the highly potent 2-pyrrolinodoxorubicin conjugated to antibodies for targeted therapy of cancer |
WO2015047510A1 (en) | 2013-09-27 | 2015-04-02 | Immunomedics, Inc. | Anti-trop-2 antibody-drug conjugates and uses thereof |
US20150118222A1 (en) | 2013-10-25 | 2015-04-30 | Pharmacyclics, Inc. | Treatment using bruton's tyrosine kinase inhibitors and immunotherapy |
WO2015069430A2 (en) | 2013-11-05 | 2015-05-14 | Immunomedics, Inc. | Humanized anti-ceacam5 antibody and uses thereof |
WO2016028896A1 (en) | 2014-08-19 | 2016-02-25 | Novartis Ag | Anti-cd123 chimeric antigen receptor (car) for use in cancer treatment |
US20160095939A1 (en) | 2014-10-07 | 2016-04-07 | Immunomedics, Inc. | Neoadjuvant use of antibody-drug conjugates |
WO2016210108A1 (en) | 2015-06-25 | 2016-12-29 | Immunomedics, Inc. | Combining anti-hla-dr or anti-trop-2 antibodies with microtubule inhibitors, parp inhibitors, bruton kinase inhibitors or phosphoinositide 3-kinase inhibitors significantly improves therapeutic outcome in cancer |
US10058621B2 (en) * | 2015-06-25 | 2018-08-28 | Immunomedics, Inc. | Combination therapy with anti-HLA-DR antibodies and kinase inhibitors in hematopoietic cancers |
Non-Patent Citations (342)
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